Reprogramming the tumor microenvironment in MSS CRC: the role of TKIs in combination with immunotherapy

Immunotherapy has revolutionized the treatment landscape of colorectal cancer (CRC), improving clinical outcomes in microsatellite instability-high tumors. In contrast, microsatellite stable (MSS) CRC exhibits intrinsic resistance to immune checkpoint inhibitors (ICIs), driven by reduced neoantigen load, resulting in an immunologically ‘cold' tumor microenvironment (TME). To overcome these barriers, combination strategies integrating ICIs with tyrosine kinase inhibitors (TKIs) have been investigated based on their ability to inhibit multiple oncogenic and angiogenic signaling pathways. Beyond their antiangiogenic effects, preclinical evidence has demonstrated that TKIs can induce immunological reprogramming of the TME, promoting proinflammatory macrophage polarization, antigen presentation, vascular normalization, and T-cell infiltration. This evidence supported several early-phase clinical trials evaluating TKI-ICI combinations, showing encouraging signals of clinical activity in refractory MSS CRC. Recently, the interim analysis of the phase III STELLAR-303 trial demonstrated an overall survival benefit with the combination of zanzalintinib plus atezolizumab compared with regorafenib in pretreated MSS CRC. Notably, a consistent exploratory finding across the TKI-ICI trials was the potential role of liver metastases in driving local and systemic immunosuppression. Preclinical MSS CRC mouse models confirmed this suggestion, highlighting the association between the presence of liver metastases and impaired effector T-cell responses and antigen presentation. Overall, the heterogeneity of clinical outcomes underscores the complexity of immune resistance in MSS CRC and supports the development of multimodal biomarkers integrating spatial pathology, immune profiling, and artificial intelligence. This review discusses current preclinical and clinical evidence on TKI-ICI combinations in MSS CRC, exploring emerging mechanisms of immune resistance and potential therapeutic vulnerabilities.