The evolution of immunotherapy resistance in mismatch repair-deficient colorectal cancer: A spatiotemporal perspective.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape for mismatch repair deficient (dMMR) colorectal cancer; however, primary and acquired resistance remain significant challenges in clinical practice. This review proposes a working hypothesis that resistance can be conceptualized as following an evolutionary trajectory from a dynamic spatiotemporal perspective: commencing with early immune evasion by tumor cells, progressing through an adaptive immunosuppression phase, and culminating in advanced metastatic resistance characterized by spatial heterogeneity. Within this framework, we critically evaluate combination therapeutic strategies targeting resistance signals at each stage, including dual immune checkpoint blockade, tumor microenvironment modulators, novel bispecific antibodies, and neoantigen vaccines. We further emphasize that future breakthroughs will depend on leveraging single-cell multi-omics and spatial transcriptomics technologies to unravel resistance heterogeneity. This will drive the development of dynamic, personalized sequential combination therapies, delivering sustained benefits for patients.