Cytokine‑Driven Modulation of Immune Checkpoint Therapy Response in Colorectal Cancer

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape for a subset of patients with colorectal cancer (CRC), particularly those with mismatch repair‑deficient/microsatellite‑instability-high (dMMR/MSI‑H) subtype. Nevertheless, most CRCs with mismatch repair‑proficient (pMMR)/microsatellite‑stable (MSS) subtype remain intrinsically resistant to ICIs, and even initially responsive dMMR/MSS CRCs frequently develop acquired resistance, substantially limiting their effectiveness. Therefore, overcoming resistance has become a major clinical challenge and a central focus of research in ICI‑treated unresectable or metastatic CRCs. Emerging evidence highlights that cytokines can critically modulate ICI effectiveness by influencing immune checkpoint expression, shaping the tumor microenvironment (TME), regulating immunosuppressive cell populations and functions, and modulating cancer stem cell behaviors in preclinical CRC models, offering promising avenues to enhance therapeutic responses. In this review, we summarize recent advances from preclinical studies and explore the potential of cytokines, as both the activators and inhibitors, to modulate drug resistance. These insights may help guide the development of combinational immunotherapeutic strategies aimed at enhancing patient responses to ICIs in CRC.