CD8⁺ T cells are involved in the pathogenesis of inflammatory bowel disease (IBD), a complex multifactorial chronic disease. Here, we present an overview of the current research with the controversial findings of CD8⁺ T cell subsets and discuss some possible perspectives on their therapeutic value in IBD. Studies on the role of CD8⁺ T cells in IBD have contradictory outcomes, which might be related to the heterogeneity of the cells. Recent data suggest that cytotoxic CD8⁺ T cells (Tc1) and interleukin (IL) 17-producing CD8⁺ (Tc17) cells contribute to the pathogenesis of IBD. Moreover, subsets of regulatory CD8⁺ T cells are abundant at sites of inflammation and can exhibit pro-inflammatory features. Some subsets of tissue resident memory CD8⁺ T cells (Trm) might be immunosuppressant, whereas others might be pro-inflammatory. Lastly, exhausted T cells might indicate a positive outcome for patients. The function and plasticity of different subsets of CD8⁺ T cells in health and IBD remain to be further investigated in a challenging field due to the limited availability of mucosal samples and adequate controls.

The advent of immune checkpoint blockade (ICB) has transformed cancer immunotherapy, enabling remarkable long-term outcomes and improved survival, particularly with ICB combination treatments. However, clinical benefits remain confined to a subset of patients, and life-threatening immune-related adverse effects pose a significant challenge. This limited efficacy is attributed to cancer heterogeneity, which is mediated by ligand–receptor interactions, exosomes, secreted factors, and key transcription factors. Oncogenic regulators like E2F1 and MYC drive metastatic tumor environments and intertwine with immunoregulatory pathways, impairing T cell function and reducing immunotherapy effectiveness. To address these challenges, FDA-approved biomarkers, such as tumor mutational burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression, help to identify patients most likely to benefit from ICB. Yet, current biomarkers have limitations, making treatment decisions difficult. Recently, T cells—the primary target of ICB—have emerged as promising biomarkers. This review explores the relationship between cancer drivers and immune response, and emphasizes the role of CD8+ T cells in predicting and monitoring ICB efficacy. Tumor-infiltrating CD8+ T cells correlate with positive clinical outcomes in many cancers, yet obtaining tumor tissue remains complex, limiting its practical use. Conversely, circulating T cell subsets are more accessible and have shown promise as predictive biomarkers. Specifically, memory and progenitor exhausted T cells are associated with favorable immunotherapy responses, while terminally exhausted T cells negatively correlate with ICB efficacy. Ultimately, combining biomarkers enhances predictive accuracy, as demonstrated by integrating TMB/PD-L1 expression with CD8+ T cell frequency. Computational models incorporating cancer and immune signatures could further refine patient stratification, advancing personalized immunotherapy.