Immunotherapy and novel combination strategies in metastatic colorectal cancer: overcoming resistance and expanding treatment opportunities

Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related mortality worldwide. While significant advances have been achieved with cytotoxic chemotherapy, targeted therapies (anti-VEGF and anti-EGFR agents), and optimized molecular stratification, long-term outcomes remain unsatisfactory for most patients. Immunotherapy has revolutionized the treatment landscape in several malignancies; however, in colorectal cancer its benefit has been largely confined to the small subset of patients with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) tumors. The vast majority of mCRC cases are microsatellite stable (MSS) and display intrinsic resistance to immune checkpoint inhibitors. A deeper understanding of tumor biology, immune microenvironment interactions, and resistance mechanisms is therefore critical to expanding the therapeutic impact of immunotherapy in this disease.This Research Topic aims to address the critical challenge of primary and acquired resistance to immunotherapy in metastatic colorectal cancer. Despite the remarkable efficacy of immune checkpoint inhibitors in dMMR/MSI-H tumors, MSS mCRC continues to represent a major unmet clinical need. Recent advances in molecular profiling, translational immunology, and combination treatment strategies have opened new opportunities to enhance immunogenicity and overcome immune evasion. Potential strategies include combining immunotherapy with chemotherapy, radiotherapy, anti-angiogenic agents, targeted therapies, cancer vaccines, oncolytic viruses, and novel immunomodulatory compounds. Furthermore, biomarker-driven patient selection, tumor microenvironment modulation, and innovative trial designs are crucial to improve therapeutic outcomes. The goal of this Research Topic is to provide a comprehensive and updated overview of emerging biological insights, translational research findings, and clinical trial results that may redefine treatment paradigms and expand the benefit of immunotherapy to a broader population of patients with mCRC.This Research Topic welcomes contributions addressing translational, clinical, and methodological advances in immunotherapy for metastatic colorectal cancer. Areas of interest include, but are not limited to:• Mechanisms of immune resistance in MSS and MSI-H mCRC• Tumor microenvironment and immune landscape characterization• Novel immunotherapy combinations (chemotherapy, targeted therapy, radiotherapy, anti-angiogenic agents)• Biomarkers predictive of response or resistance• Adoptive cell therapies, bispecific antibodies, and cancer vaccines• Microbiome interactions and immunotherapy response• Innovative clinical trial designs and real-world dataWe welcome Original Research Articles, Reviews, Mini-Reviews, Systematic Reviews, Clinical Trial Reports, Translational Research studies, and Perspectives that provide innovative insights and clinically relevant data.Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic. Topic editors: Maria Maddalena Laterza, Claudia Cardone Source: https://www.frontiersin.org/research-topics/78399/immunotherapy-and-novel-combination-strategies-in-metastatic-colorectal-cancer-overcoming-resistance-and-expanding-treatment-opportunities