Myeloid-derived suppressor cells and regulatory T cells in colorectal cancer: a synergistic immunosuppressive axis and emerging therapeutic opportunities

Microsatellite-stable (MSS)/proficient mismatch-repair (pMMR) colorectal cancer (CRC) accounts for more than 85% of cases but responds poorly to single-agent immune checkpoint inhibitors (ICIs), with objective response rates remaining below 5%. A principal barrier to effective immunotherapy in these tumors is a durable immunosuppressive axis formed by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) within the tumor microenvironment. This axis impedes antitumor immunity through multilayered mechanisms including bidirectional chemotactic recruitment, reciprocal cytokine signaling, metabolic suppression and exosome-mediated communication. CRC is uniquely influenced by the gut microbiota: Fusobacterium nucleatum promotes MDSC/Treg enrichment via TLR4-NF-κB and Fap2-TIGIT pathways; Peptostreptococcus anaerobius acts through integrin-PI3K-NF-κB signaling; and microbial metabolites such as 4-HPA activate JAK2/STAT3-CXCL3 signaling to expand MDSC populations. Concurrently, a hypoxia-lactate-HIF-1α-CD73/A2AR circuit further stabilizes suppressive phenotypes, forming a "microbiota-metabolism-hypoxia-MDSC-Treg" cascade. Emerging clinical and translational data indicate that disrupting this axis can sensitize MSS-CRC to ICIs: for example, Zanzalintinib combined with Atezolizumab reported survival benefit in the STELLAR-303 trial, and dual blockade of novel checkpoints with PD-(L)1 has been associated with enhanced immune activation in solid tumors. Targeting the MDSC-Treg axis therefore represents a promising strategy to overcome immunotherapy resistance in MSS/pMMR CRC.