Topic: Immunotherapy in Colorectal Cancer: Current Status and Future Directions

Colorectal cancer (CRC) remains one of the most prevalent and challenging malignancies worldwide. In recent years, its therapeutic landscape has undergone a paradigm shift, largely driven by breakthroughs in immunotherapy. Immune checkpoint inhibitors (ICIs) have demonstrated remarkable success in a subset of patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) tumors. However, the vast majority of patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) disease derive limited benefit from these therapies. This pronounced disparity highlights an urgent need to deepen our understanding of the tumor immune microenvironment (TIME), identify novel predictive biomarkers, and develop innovative strategies to overcome both primary and acquired resistance to immunotherapy.

This Special Issue aims to compile a comprehensive collection of high-quality original research and review articles that illuminate the evolving landscape of immunotherapy in CRC. We seek to explore the mechanistic underpinnings of therapeutic response and resistance, evaluate current clinical applications, and chart a course for future therapeutic innovations. By synthesizing the latest preclinical and clinical research, this issue seeks to provide a roadmap for expanding the applicability and efficacy of immunotherapy to benefit a broader population of patients with CRC.

Potential topics:

● Mechanisms of Response and Resistance

    ♦ Characteristics of the TIMEin pMMR/MSS CRC;

    ♦ Role of the gut microbiome in modulating immunotherapy response;

    ♦ Mechanisms of primary and acquired resistance to immune checkpoint blockade.

● Biomarkers and Patient Stratification

   ♦ Beyond MSI: Novel predictive biomarkers for immunotherapy;

   ♦ Liquid biopsy and circulating immune markers;

   ♦ Integrative genomic and transcriptomic profiling.

● Innovative Therapeutic Strategies

  ♦ Novel immune checkpoint targets (e.g., lymphocyte activation gene-3(LAG-3), T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3));

  ♦ Adoptive cell therapies, including chimeric antigen receptor T-cell (CAR-T)therapy, T-cell receptor–engineered T-cell (TCR-T) therapy, and tumor-infiltrating lymphocyte (TIL) therapy, in CRC;

  ♦ Cancer vaccines and neoantigen-based therapies.

● Combination Therapies

  ♦ Immunotherapy in combination with chemotherapy, targeted therapy, or radiotherapy;

  ♦ Rational combinations of multiple immunotherapeutic agents;

  ♦ Strategies to normalize tumor vasculature and enhance immune infiltration.

● Clinical Trials and Translational Research

  ♦ Outcomes and biomarkers from recent and ongoing clinical trials;

  ♦ Real-world evidence on the effectiveness of approved immunotherapies;

  ♦ Management of immune-related adverse events (irAEs) in CRC patients.

Colorectal cancer, immunotherapy, immune checkpoint inhibitors, tumor immune microenvironment, microsatellite instability, biomarkers, combination therapy, adoptive cell transfer