Next-generation precision oncology in microsatellite stable colorectal cancer: integrated targeting beyond RAS and RAF

The therapeutic landscape of colorectal cancer (CRC) has evolved with the identification of molecular subtypes, including mismatch repair-deficient/microsatellite instability-high, POLE mutations, RAS/BRAF alterations, and HER2 amplification, enabling use of precision therapies and immune checkpoint inhibitors for selected populations. However, most microsatellite-stable (MSS) tumors remain resistant due to tumor heterogeneity, adaptive resistance, and an immunosuppressive tumor microenvironment (TME). Advances in molecular profiling, spatial biology, and immune characterization have revealed vulnerabilities beyond canonical signaling, facilitating novel strategies such as antibody-drug conjugates (ADCs), bispecific antibodies, DNA damage response (DDR) targeting, TME-directed therapies, cellular therapies, and epigenetic modulation. HER2-directed ADCs, notably trastuzumab deruxtecan, have shown clinically meaningful activity in HER2-positive metastatic CRC, providing proof of concept for ADC-based therapy. Additional targets under investigation include CEACAM5, LGR5, EGFR, HER3, MET, B7-H3, and CDH17. Bispecific antibodies and co-stimulatory agonists are being developed to overcome antigen heterogeneity and pathway redundancy, with the EGFR-MET bispecific antibody amivantamab showing initial clinical efficacy. Moreover, next-generation immune checkpoint inhibitors and multitarget combinations aim to reinvigorate T-cell responses in MSS tumors. Early chimeric antigen receptor T-cell studies targeting CEA and GUCY2C demonstrate feasibility and manageable toxicity, although tumor-intrinsic and TME barriers persist. Emerging strategies increasingly focus on modulating the TME to enhance immune infiltration and effector function, targeting CCR8, TGF-β, adenosine, CSF1R, CXCR1/2, STING, and CD47. DDR and epigenetic therapies offer additional opportunities to sensitize resistant tumors. Integrated, multidimensional biomarker approaches and artificial intelligence-driven interpretation of tumor and TME features are expected to guide personalized therapy, anticipate resistance, and broaden the benefit of targeted and immune-based interventions in CRC.