Unraveling Signaling Pathways in Immune Microenvironment Crosstalk to Overcome Immunotherapy Resistance in Colorectal Cancer

As a major cause of cancer-related death globally, colorectal cancer (CRC) remains largely refractory to immunotherapy outside the context of microsatellite instability-high (MSI-H). This limited efficacy stems largely from the complex crosstalk within the tumor microenvironment (TME), which fosters immunosuppression and resistance. Our review analyzes the impact of dysregulated pathways-such as PD-1/PD-L1, cGAS/STING, Notch, and cytokine signaling-on the functional states of T cells, B cells, macrophages, dendritic cells, and NK cells in CRC. We investigate how these pathways underpin critical processes such as immune evasion, T cell exhaustion, and the protumor polarization of innate immune cells, thereby fostering a permissive niche for tumor growth and resistance to checkpoint inhibitors. The discussion also covers emerging biomarkers and innovative strategies, including combination therapies targeting pivotal signaling nodes, to reprogram the immune landscape. A deeper mechanistic understanding of these immunoregulatory pathways is essential for developing effective treatments to overcome resistance and improve patient prognosis.