<?xml version="1.0" encoding="us-ascii"?>
<!-- DFIN ActiveDisclosure(SM) XBRL Linkbase Document - http://www.dfinsolutions.com/ -->
<!-- Creation Date      : 2021-11-08T23:15:43.6385474+00:00 -->
<!-- Version            : 5.0.1.702 -->
<!-- Package ID         : 60eea23e33e74f9d927d497d1e2f95ee -->
<!-- Copyright (c) 2021 Donnelley Financial Solutions, Inc. All Rights Reserved. -->
<link:linkbase xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd">
  <link:roleRef xlink:type="simple" xlink:href="cccc-20210930.xsd#TemplateLink" roleURI="http://c4therapeutics.com/20210930/role/TemplateLink" />
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/StatementCondensedConsolidatedBalanceSheets" xlink:href="cccc-20210930.xsd#Role_StatementCondensedConsolidatedBalanceSheets" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/StatementCondensedConsolidatedBalanceSheets">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PrepaidExpenseAndOtherAssetsCurrent" xlink:type="locator" xlink:label="us-gaap_PrepaidExpenseAndOtherAssetsCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccountsReceivableNetCurrent" xlink:type="locator" xlink:label="us-gaap_AccountsReceivableNetCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_MarketableSecuritiesCurrent" xlink:type="locator" xlink:label="us-gaap_MarketableSecuritiesCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CashAndCashEquivalentsAtCarryingValue" xlink:type="locator" xlink:label="us-gaap_CashAndCashEquivalentsAtCarryingValue" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OtherAssetsNoncurrent" xlink:type="locator" xlink:label="us-gaap_OtherAssetsNoncurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RestrictedCashAndCashEquivalentsNoncurrent" xlink:type="locator" xlink:label="us-gaap_RestrictedCashAndCashEquivalentsNoncurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingLeaseRightOfUseAsset" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseRightOfUseAsset" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentNet" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_MarketableSecuritiesNoncurrent" xlink:type="locator" xlink:label="us-gaap_MarketableSecuritiesNoncurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AssetsCurrent" xlink:type="locator" xlink:label="us-gaap_AssetsCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_Assets" xlink:type="locator" xlink:label="us-gaap_Assets" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingLeaseLiabilityCurrent" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseLiabilityCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DeferredRevenueCurrent" xlink:type="locator" xlink:label="us-gaap_DeferredRevenueCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccruedLiabilitiesAndOtherLiabilities" xlink:type="locator" xlink:label="us-gaap_AccruedLiabilitiesAndOtherLiabilities" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccountsPayableCurrent" xlink:type="locator" xlink:label="us-gaap_AccountsPayableCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LongTermDebtNoncurrent" xlink:type="locator" xlink:label="us-gaap_LongTermDebtNoncurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingLeaseLiabilityNoncurrent" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseLiabilityNoncurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DeferredRevenueNoncurrent" xlink:type="locator" xlink:label="us-gaap_DeferredRevenueNoncurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LiabilitiesCurrent" xlink:type="locator" xlink:label="us-gaap_LiabilitiesCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RetainedEarningsAccumulatedDeficit" xlink:type="locator" xlink:label="us-gaap_RetainedEarningsAccumulatedDeficit" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax" xlink:type="locator" xlink:label="us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AdditionalPaidInCapitalCommonStock" xlink:type="locator" xlink:label="us-gaap_AdditionalPaidInCapitalCommonStock" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CommonStockValue" xlink:type="locator" xlink:label="us-gaap_CommonStockValue" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PreferredStockValue" xlink:type="locator" xlink:label="us-gaap_PreferredStockValue" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_StockholdersEquity" xlink:type="locator" xlink:label="us-gaap_StockholdersEquity" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CommitmentsAndContingencies" xlink:type="locator" xlink:label="us-gaap_CommitmentsAndContingencies" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_Liabilities" xlink:type="locator" xlink:label="us-gaap_Liabilities" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LiabilitiesAndStockholdersEquity" xlink:type="locator" xlink:label="us-gaap_LiabilitiesAndStockholdersEquity" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesAndStockholdersEquity" xlink:to="us-gaap_Liabilities" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesAndStockholdersEquity" xlink:to="us-gaap_CommitmentsAndContingencies" order="10020.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesAndStockholdersEquity" xlink:to="us-gaap_StockholdersEquity" order="10030.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_StockholdersEquity" xlink:to="us-gaap_PreferredStockValue" order="10040.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_StockholdersEquity" xlink:to="us-gaap_CommonStockValue" order="10050.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_StockholdersEquity" xlink:to="us-gaap_AdditionalPaidInCapitalCommonStock" order="10060.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_StockholdersEquity" xlink:to="us-gaap_AccumulatedOtherComprehensiveIncomeLossNetOfTax" order="10070.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_StockholdersEquity" xlink:to="us-gaap_RetainedEarningsAccumulatedDeficit" order="10080.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Liabilities" xlink:to="us-gaap_LiabilitiesCurrent" order="10090.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Liabilities" xlink:to="us-gaap_DeferredRevenueNoncurrent" order="10100.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Liabilities" xlink:to="us-gaap_OperatingLeaseLiabilityNoncurrent" order="10110.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Liabilities" xlink:to="us-gaap_LongTermDebtNoncurrent" order="10120.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesCurrent" xlink:to="us-gaap_AccountsPayableCurrent" order="10130.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesCurrent" xlink:to="us-gaap_AccruedLiabilitiesAndOtherLiabilities" order="10140.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesCurrent" xlink:to="us-gaap_DeferredRevenueCurrent" order="10150.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LiabilitiesCurrent" xlink:to="us-gaap_OperatingLeaseLiabilityCurrent" order="10160.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_AssetsCurrent" order="10170.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_MarketableSecuritiesNoncurrent" order="10180.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_PropertyPlantAndEquipmentNet" order="10190.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_OperatingLeaseRightOfUseAsset" order="10200.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_RestrictedCashAndCashEquivalentsNoncurrent" order="10210.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_Assets" xlink:to="us-gaap_OtherAssetsNoncurrent" order="10220.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AssetsCurrent" xlink:to="us-gaap_CashAndCashEquivalentsAtCarryingValue" order="10230.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AssetsCurrent" xlink:to="us-gaap_MarketableSecuritiesCurrent" order="10240.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AssetsCurrent" xlink:to="us-gaap_AccountsReceivableNetCurrent" order="10250.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AssetsCurrent" xlink:to="us-gaap_PrepaidExpenseAndOtherAssetsCurrent" order="10260.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/StatementCondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss" xlink:href="cccc-20210930.xsd#Role_StatementCondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/StatementCondensedConsolidatedStatementsOfOperationsAndComprehensiveLoss">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_GeneralAndAdministrativeExpense" xlink:type="locator" xlink:label="us-gaap_GeneralAndAdministrativeExpense" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ResearchAndDevelopmentExpense" xlink:type="locator" xlink:label="us-gaap_ResearchAndDevelopmentExpense" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingExpenses" xlink:type="locator" xlink:label="us-gaap_OperatingExpenses" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_RevenueFromCollaborativeArrangementExcludingRevenueFromContractWithCustomer" xlink:type="locator" xlink:label="us-gaap_RevenueFromCollaborativeArrangementExcludingRevenueFromContractWithCustomer" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_FairValueAdjustmentOfWarrants" xlink:type="locator" xlink:label="us-gaap_FairValueAdjustmentOfWarrants" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_InterestAndOtherIncome" xlink:type="locator" xlink:label="us-gaap_InterestAndOtherIncome" />
    <link:loc xlink:href="cccc-20210930.xsd#cccc_InterestExpenseAndAmortizationOfLongTermDebtRelatedParty" xlink:type="locator" xlink:label="cccc_InterestExpenseAndAmortizationOfLongTermDebtRelatedParty" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_NonoperatingIncomeExpense" xlink:type="locator" xlink:label="us-gaap_NonoperatingIncomeExpense" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingIncomeLoss" xlink:type="locator" xlink:label="us-gaap_OperatingIncomeLoss" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:type="locator" xlink:label="us-gaap_IncomeTaxExpenseBenefit" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:type="locator" xlink:label="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_MarketableSecuritiesUnrealizedGainLoss" xlink:type="locator" xlink:label="us-gaap_MarketableSecuritiesUnrealizedGainLoss" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ComprehensiveIncomeNetOfTax" xlink:type="locator" xlink:label="us-gaap_ComprehensiveIncomeNetOfTax" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PreferredStockDividendsIncomeStatementImpact" xlink:type="locator" xlink:label="us-gaap_PreferredStockDividendsIncomeStatementImpact" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_NetIncomeLoss" xlink:type="locator" xlink:label="us-gaap_NetIncomeLoss" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" xlink:type="locator" xlink:label="us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" xlink:to="us-gaap_NetIncomeLoss" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" xlink:to="us-gaap_PreferredStockDividendsIncomeStatementImpact" order="10020.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_ComprehensiveIncomeNetOfTax" xlink:to="us-gaap_NetIncomeLoss" order="10030.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_ComprehensiveIncomeNetOfTax" xlink:to="us-gaap_MarketableSecuritiesUnrealizedGainLoss" order="10040.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetIncomeLoss" xlink:to="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" order="10050.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetIncomeLoss" xlink:to="us-gaap_IncomeTaxExpenseBenefit" order="10060.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:to="us-gaap_OperatingIncomeLoss" order="10070.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:to="us-gaap_NonoperatingIncomeExpense" order="10080.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NonoperatingIncomeExpense" xlink:to="cccc_InterestExpenseAndAmortizationOfLongTermDebtRelatedParty" order="10090.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NonoperatingIncomeExpense" xlink:to="us-gaap_InterestAndOtherIncome" order="10100.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NonoperatingIncomeExpense" xlink:to="us-gaap_FairValueAdjustmentOfWarrants" order="10110.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_OperatingIncomeLoss" xlink:to="us-gaap_RevenueFromCollaborativeArrangementExcludingRevenueFromContractWithCustomer" order="10120.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_OperatingIncomeLoss" xlink:to="us-gaap_OperatingExpenses" order="10130.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_OperatingExpenses" xlink:to="us-gaap_ResearchAndDevelopmentExpense" order="10140.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_OperatingExpenses" xlink:to="us-gaap_GeneralAndAdministrativeExpense" order="10150.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/StatementCondensedConsolidatedStatementsOfCashFlows" xlink:href="cccc-20210930.xsd#Role_StatementCondensedConsolidatedStatementsOfCashFlows" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/StatementCondensedConsolidatedStatementsOfCashFlows">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_IncreaseDecreaseInDeferredRevenue" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInDeferredRevenue" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_IncreaseDecreaseInOperatingLeaseLiability" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInOperatingLeaseLiability" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_IncreaseDecreaseInAccountsPayable" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInAccountsPayable" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_IncreaseDecreaseInAccountsReceivable" xlink:type="locator" xlink:label="us-gaap_IncreaseDecreaseInAccountsReceivable" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_FairValueAdjustmentOfWarrants" xlink:type="locator" xlink:label="us-gaap_FairValueAdjustmentOfWarrants" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AmortizationOfDebtDiscountPremium" xlink:type="locator" xlink:label="us-gaap_AmortizationOfDebtDiscountPremium" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments" xlink:type="locator" xlink:label="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_Depreciation" xlink:type="locator" xlink:label="us-gaap_Depreciation" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ShareBasedCompensation" xlink:type="locator" xlink:label="us-gaap_ShareBasedCompensation" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ProfitLoss" xlink:type="locator" xlink:label="us-gaap_ProfitLoss" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" xlink:type="locator" xlink:label="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsToAcquireMarketableSecurities" xlink:type="locator" xlink:label="us-gaap_PaymentsToAcquireMarketableSecurities" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ProceedsFromSaleAndMaturityOfMarketableSecurities" xlink:type="locator" xlink:label="us-gaap_ProceedsFromSaleAndMaturityOfMarketableSecurities" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ProceedsFromPaymentsForOtherFinancingActivities" xlink:type="locator" xlink:label="us-gaap_ProceedsFromPaymentsForOtherFinancingActivities" />
    <link:loc xlink:href="cccc-20210930.xsd#cccc_PaymentsForVestedStockOptionSettlement" xlink:type="locator" xlink:label="cccc_PaymentsForVestedStockOptionSettlement" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsForRepurchaseOfCommonStock" xlink:type="locator" xlink:label="us-gaap_PaymentsForRepurchaseOfCommonStock" />
    <link:loc xlink:href="cccc-20210930.xsd#cccc_ProceedsFromIssuanceOfLongTermDebtAndWarrant" xlink:type="locator" xlink:label="cccc_ProceedsFromIssuanceOfLongTermDebtAndWarrant" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ProceedsFromIssuanceOfConvertiblePreferredStock" xlink:type="locator" xlink:label="us-gaap_ProceedsFromIssuanceOfConvertiblePreferredStock" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PaymentsForRepurchaseOfInitialPublicOffering" xlink:type="locator" xlink:label="us-gaap_PaymentsForRepurchaseOfInitialPublicOffering" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_ProceedsFromStockOptionsExercised" xlink:type="locator" xlink:label="us-gaap_ProceedsFromStockOptionsExercised" />
    <link:loc xlink:href="cccc-20210930.xsd#cccc_ProceedsFromIssuanceOfFollowOnOffering" xlink:type="locator" xlink:label="cccc_ProceedsFromIssuanceOfFollowOnOffering" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivities" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivities" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:type="locator" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivities" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseExcludingExchangeRateEffect" xlink:type="locator" xlink:label="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseExcludingExchangeRateEffect" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseExcludingExchangeRateEffect" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivities" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseExcludingExchangeRateEffect" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivities" order="10020.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseExcludingExchangeRateEffect" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivities" order="10030.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="cccc_ProceedsFromIssuanceOfFollowOnOffering" order="10040.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="us-gaap_ProceedsFromStockOptionsExercised" order="10050.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="us-gaap_PaymentsForRepurchaseOfInitialPublicOffering" order="10060.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="us-gaap_ProceedsFromIssuanceOfConvertiblePreferredStock" order="10070.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="cccc_ProceedsFromIssuanceOfLongTermDebtAndWarrant" order="10080.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="us-gaap_PaymentsForRepurchaseOfCommonStock" order="10090.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="cccc_PaymentsForVestedStockOptionSettlement" order="10100.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:to="us-gaap_ProceedsFromPaymentsForOtherFinancingActivities" order="10110.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="us-gaap_ProceedsFromSaleAndMaturityOfMarketableSecurities" order="10120.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="us-gaap_PaymentsToAcquireMarketableSecurities" order="10130.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:to="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" order="10140.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_ProfitLoss" order="10150.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_ShareBasedCompensation" order="10160.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_Depreciation" order="10170.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense" order="10180.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_AccretionAmortizationOfDiscountsAndPremiumsInvestments" order="10190.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_AmortizationOfDebtDiscountPremium" order="10200.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_FairValueAdjustmentOfWarrants" order="10210.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_IncreaseDecreaseInAccountsReceivable" order="10220.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets" order="10230.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_IncreaseDecreaseInAccountsPayable" order="10240.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities" order="10250.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_IncreaseDecreaseInOperatingLeaseLiability" order="10260.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:to="us-gaap_IncreaseDecreaseInDeferredRevenue" order="10270.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureMarketableSecuritiesSummaryOfMarketableSecuritiesDetails" xlink:href="cccc-20210930.xsd#Role_DisclosureMarketableSecuritiesSummaryOfMarketableSecuritiesDetails" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureMarketableSecuritiesSummaryOfMarketableSecuritiesDetails">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AvailableForSaleSecuritiesDebtSecurities" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleSecuritiesDebtSecurities" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" xlink:type="locator" xlink:label="us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" xlink:to="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedGainBeforeTax" order="10010.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" xlink:to="us-gaap_AvailableForSaleDebtSecuritiesAccumulatedGrossUnrealizedLossBeforeTax" order="10020.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AvailableForSaleDebtSecuritiesAmortizedCostBasis" xlink:to="us-gaap_AvailableForSaleSecuritiesDebtSecurities" order="10030.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/DisclosurePropertyAndEquipmentSummaryOfPropertyAndEquipmentDetails" xlink:href="cccc-20210930.xsd#Role_DisclosurePropertyAndEquipmentSummaryOfPropertyAndEquipmentDetails" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/DisclosurePropertyAndEquipmentSummaryOfPropertyAndEquipmentDetails">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" xlink:type="locator" xlink:label="us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PropertyPlantAndEquipmentGross" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentGross" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_PropertyPlantAndEquipmentNet" xlink:type="locator" xlink:label="us-gaap_PropertyPlantAndEquipmentNet" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_PropertyPlantAndEquipmentNet" xlink:to="us-gaap_PropertyPlantAndEquipmentGross" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_PropertyPlantAndEquipmentNet" xlink:to="us-gaap_AccumulatedDepreciationDepletionAndAmortizationPropertyPlantAndEquipment" order="10020.00" priority="2" use="optional" weight="-1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureLeasesSummaryOfLeaseCostsDetails" xlink:href="cccc-20210930.xsd#Role_DisclosureLeasesSummaryOfLeaseCostsDetails" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureLeasesSummaryOfLeaseCostsDetails">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_VariableLeaseCost" xlink:type="locator" xlink:label="us-gaap_VariableLeaseCost" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingLeaseCost" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseCost" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LeaseCost" xlink:type="locator" xlink:label="us-gaap_LeaseCost" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LeaseCost" xlink:to="us-gaap_OperatingLeaseCost" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LeaseCost" xlink:to="us-gaap_VariableLeaseCost" order="10020.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureLeasesUndiscountedMinimumFutureLeasePaymentsUnderNonCancelableLeasesDetails" xlink:href="cccc-20210930.xsd#Role_DisclosureLeasesUndiscountedMinimumFutureLeasePaymentsUnderNonCancelableLeasesDetails" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureLeasesUndiscountedMinimumFutureLeasePaymentsUnderNonCancelableLeasesDetails">
    <link:loc xlink:href="cccc-20210930.xsd#cccc_LesseeOperatingLeaseLiabilityPaymentsDueAfterYearFour" xlink:type="locator" xlink:label="cccc_LesseeOperatingLeaseLiabilityPaymentsDueAfterYearFour" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsRemainderOfFiscalYear" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsRemainderOfFiscalYear" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsRemainderOfFiscalYear" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths" order="10020.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo" order="10030.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearThree" order="10040.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearFour" order="10050.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="cccc_LesseeOperatingLeaseLiabilityPaymentsDueAfterYearFour" order="10060.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureLeasesUndiscountedMinimumFutureLeasePaymentsUnderNonCancelableLeasesDetails2" xlink:href="cccc-20210930.xsd#Role_DisclosureLeasesUndiscountedMinimumFutureLeasePaymentsUnderNonCancelableLeasesDetails2" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureLeasesUndiscountedMinimumFutureLeasePaymentsUnderNonCancelableLeasesDetails2">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OperatingLeaseLiability" xlink:type="locator" xlink:label="us-gaap_OperatingLeaseLiability" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:type="locator" xlink:label="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue" xlink:to="us-gaap_OperatingLeaseLiability" order="10020.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureAccruedExpensesAndOtherCurrentLiabilitiesSummaryOfAccruedExpensesAndOtherCurrentLiabilitiesDetails" xlink:href="cccc-20210930.xsd#Role_DisclosureAccruedExpensesAndOtherCurrentLiabilitiesSummaryOfAccruedExpensesAndOtherCurrentLiabilitiesDetails" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureAccruedExpensesAndOtherCurrentLiabilitiesSummaryOfAccruedExpensesAndOtherCurrentLiabilitiesDetails">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_OtherLiabilitiesCurrent" xlink:type="locator" xlink:label="us-gaap_OtherLiabilitiesCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccruedProfessionalFeesCurrent" xlink:type="locator" xlink:label="us-gaap_AccruedProfessionalFeesCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccruedEmployeeBenefitsCurrent" xlink:type="locator" xlink:label="us-gaap_AccruedEmployeeBenefitsCurrent" />
    <link:loc xlink:href="cccc-20210930.xsd#cccc_AccruedResearchAndDevelopmentCurrent" xlink:type="locator" xlink:label="cccc_AccruedResearchAndDevelopmentCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_AccruedLiabilitiesAndOtherLiabilities" xlink:type="locator" xlink:label="us-gaap_AccruedLiabilitiesAndOtherLiabilities" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesAndOtherLiabilities" xlink:to="cccc_AccruedResearchAndDevelopmentCurrent" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesAndOtherLiabilities" xlink:to="us-gaap_AccruedEmployeeBenefitsCurrent" order="10020.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesAndOtherLiabilities" xlink:to="us-gaap_AccruedProfessionalFeesCurrent" order="10030.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_AccruedLiabilitiesAndOtherLiabilities" xlink:to="us-gaap_OtherLiabilitiesCurrent" order="10040.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureCollaborationAndLicenseAgreementsScheduleOfFinancialInformationRelatedToCollaborationAndLicenseAgreementsDetails" xlink:href="cccc-20210930.xsd#Role_DisclosureCollaborationAndLicenseAgreementsScheduleOfFinancialInformationRelatedToCollaborationAndLicenseAgreementsDetails" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureCollaborationAndLicenseAgreementsScheduleOfFinancialInformationRelatedToCollaborationAndLicenseAgreementsDetails">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DeferredRevenueNoncurrent" xlink:type="locator" xlink:label="us-gaap_DeferredRevenueNoncurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DeferredRevenueCurrent" xlink:type="locator" xlink:label="us-gaap_DeferredRevenueCurrent" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DeferredRevenue" xlink:type="locator" xlink:label="us-gaap_DeferredRevenue" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_DeferredRevenue" xlink:to="us-gaap_DeferredRevenueCurrent" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_DeferredRevenue" xlink:to="us-gaap_DeferredRevenueNoncurrent" order="10020.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
  <link:roleRef roleURI="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureLongTermDebtAndWarrantRelatedPartySummaryOfAnticipatedFutureMinimumPaymentsOfLongTermDebtDetails" xlink:href="cccc-20210930.xsd#Role_DisclosureLongTermDebtAndWarrantRelatedPartySummaryOfAnticipatedFutureMinimumPaymentsOfLongTermDebtDetails" xlink:type="simple" />
  <link:calculationLink xlink:type="extended" xlink:role="http://c4therapeutics.com/20210930/taxonomy/role/DisclosureLongTermDebtAndWarrantRelatedPartySummaryOfAnticipatedFutureMinimumPaymentsOfLongTermDebtDetails">
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearThree" xlink:type="locator" xlink:label="us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearThree" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearTwo" xlink:type="locator" xlink:label="us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearTwo" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInNextTwelveMonths" xlink:type="locator" xlink:label="us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInNextTwelveMonths" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalRemainderOfFiscalYear" xlink:type="locator" xlink:label="us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalRemainderOfFiscalYear" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DebtInstrumentUnamortizedDiscountPremiumAndDebtIssuanceCostsNet" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentUnamortizedDiscountPremiumAndDebtIssuanceCostsNet" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_DebtInstrumentCarryingAmount" xlink:type="locator" xlink:label="us-gaap_DebtInstrumentCarryingAmount" />
    <link:loc xlink:href="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd#us-gaap_LongTermDebt" xlink:type="locator" xlink:label="us-gaap_LongTermDebt" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LongTermDebt" xlink:to="us-gaap_DebtInstrumentCarryingAmount" order="10010.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_LongTermDebt" xlink:to="us-gaap_DebtInstrumentUnamortizedDiscountPremiumAndDebtIssuanceCostsNet" order="10020.00" priority="2" use="optional" weight="-1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_DebtInstrumentCarryingAmount" xlink:to="us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalRemainderOfFiscalYear" order="10030.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_DebtInstrumentCarryingAmount" xlink:to="us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInNextTwelveMonths" order="10040.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_DebtInstrumentCarryingAmount" xlink:to="us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearTwo" order="10050.00" priority="2" use="optional" weight="1.00" />
    <link:calculationArc xlink:type="arc" xlink:arcrole="http://www.xbrl.org/2003/arcrole/summation-item" xlink:from="us-gaap_DebtInstrumentCarryingAmount" xlink:to="us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearThree" order="10060.00" priority="2" use="optional" weight="1.00" />
  </link:calculationLink>
</link:linkbase>
