Immunomodulatory and targeted therapies for metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) remains a major cause of cancer-related morbidity and mortality worldwide. Its systemic treatment has evolved from conventional cytotoxic chemotherapy toward biomarker-driven targeted therapy and immunotherapy. Advances in molecular profiling have refined patient selection for anti-EGFR and anti-VEGF therapies and have enabled the development of treatments directed against BRAF V600E, KRAS G12C, HER2 amplification, and other actionable alterations. In parallel, immune checkpoint inhibitors have transformed the management of microsatellite instability-high/mismatch repair-deficient mCRC, whereas microsatellite-stable disease remains largely resistant to immunotherapy and continues to require rational combination strategies. Despite these advances, primary and acquired resistance, dynamic clonal evolution, and the immunosuppressive tumor microenvironment remain major barriers to durable disease control. Circulating tumor DNA and multidimensional molecular profiling are increasingly being explored to monitor treatment response, identify emerging resistance, and guide sequential therapy. This review summarizes recent advances in targeted therapy and immunotherapy for mCRC and discusses priorities for developing adaptive, biomarker-driven treatment strategies.