Reversing T-Cell Exhaustion in Colorectal Cancer: Immunotherapeutic Strategies and Emerging Insights

Background: T-cell exhaustion (Tex) is a major immunological hurdle in colorectal cancer (CRC), particularly in microclimate-stable (MSS) sub-types where immunotherapy has limited effectiveness. This dysfunctional state of tumor-infiltrating lymphocytes—characterized by elevated expression of inhibitory receptors like PD-1, CTLA-4, and LAG-3—compromises immune-mediated tumor clearance. Immunotherapeutic strategies aimed at reversing Tex are emerging as a key avenue to improve patient response and long-term survival in CRC. Objective: This systematic review aimed to evaluate and synthesize the existing literature on immunotherapeutic interventions that target T-cell exhaustion in colorectal cancer. It sought to understand the clinical effectiveness, mechanistic insights, and safety outcomes of these interventions and assess expert opinions using a quantitative survey approach. Methods: Following PRISMA 2020 guidelines, a comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar for studies published between 2010 and 2025. A total of 40 high-quality peer-reviewed studies were included. Inclusion criteria focused on studies involving CRC patients receiving immunotherapies targeting Tex-related pathways. A structured questionnaire was also distributed to 135 experts (oncologists, immunologists, and clinical researchers) to gather perceptions on the efficacy and implementation of Tex-based immunotherapies. Responses were analyzed using descriptive statistics, correlation heatmaps, and mean scoring. Results: Review findings demonstrated that therapies such as immune checkpoint inhibitors (ICIs), CAR-T cells, and IL-15-based cytokine treatments can partially or fully reverse T-cell exhaustion, particularly in MSI-H tumors. Expert survey responses indicated strong agreement (Mean Q4 = 4.05) on the role of Tex in poor CRC prognosis and the need for combinatory immunotherapies (Mean Q3 = 3.99). Correlation analysis revealed that expert awareness was positively linked with support for adopting precision immunotherapy protocols. Most respondents (57%) had over 5 years of experience in CRC immunotherapy, and 80% favored dual or multi-targeted immune strategies. Conclusion: This review affirms that reversing T-cell exhaustion is a critical strategy to improve immunotherapy outcomes in colorectal cancer. While checkpoint inhibitors form the backbone of Tex-targeted therapy, novel approaches such as bispecific antibodies, TCR-T cells, and TME-modulating agents hold significant promise. Expert consensus emphasizes the need for biomarker-driven therapy selection, expanded training, and improved institutional protocols to enable broader clinical integration.