Drug resistance-driven cytokine alterations in the immunosuppressive microenvironment of colorectal cancer

Colorectal cancer (CRC), the third most prevalent malignancy globally, confronts a critical clinical hurdle of drug resistance, which leads to treatment failure in over 90% of metastatic cases. This highlights the pressing necessity to decipher and counteract resistance mechanisms. Cancer cells often acquire intrinsic or adaptive resistance to clinical anticancer agents, severely undermining therapeutic efficacy. A key driver of this resistance is the tumor microenvironment (TME), a dynamic ecosystem rich in extracellular cytokines that form complex communication networks. These networks coordinate essential cancer hallmarks, shape pharmacological responses, and promote the evolution of acquired resistance. A systems-level understanding of TME-derived cytokine-mediated resistance mechanisms offers unprecedented opportunities to identify novel therapeutic targets and design effective combination strategies. This review provides a comprehensive analysis of cytokine-driven resistance pathways in CRC, critically evaluates emerging therapeutic interventions aimed at overcoming resistance, and discusses major translational challenges. By integrating current knowledge within a systems biology framework and delineating future research priorities, this work lays a foundation for developing innovative strategies to surmount treatment resistance and enhance clinical outcomes for CRC patients.