Key Findings:

• While around 90% of metastatic colorectal cancers (mCRC) are microsatellite stable (MSS) and resistant to immune checkpoint inhibition, chemotherapy-mediated immune stimulation in MSS CRC has been observed in preclinical models and clinical trials.
• Using in vitro and mouse models of MSS and MSI CRC as well as clinical specimens of chemotherapy-treated MSS mCRC patients, a mechanism specific to the FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) regimen was uncovered by which CD8+ T cell infiltration into MSS mCRC tumors is enhanced, but their activation is halted, potentially by suppression of cytokine GM-CSF and/or depletion of type 1 conventional dendritic cells (cDC1) in the tumor microenvironment (TME).
• These findings contribute to our understanding of the mechanisms of chemotherapy-dependent immune modulation and bring the field closer to harnessing these effects for therapeutic gain.