Immunotherapy Resistance in Solid Tumors: Mechanisms and Therapeutic Strategies

Immune checkpoint inhibitors (ICIs) have reshaped the treatment of many solid malignancies, producing durable remissions in patients who previously had few options. Yet most patients either never respond (primary resistance) or relapse after an initial benefit (acquired resistance). Resistance is not a single phenomenon. It arises from a layered set of tumor-intrinsic programs, an immunosuppressive and often physically exclusionary tumor microenvironment (TME), progressive dysfunction of tumor-reactive T cells, and host-level factors such as the gut microbiome, systemic inflammation and prior therapies. This review integrates current knowledge of these mechanisms, following the sequence of the cancer-immunity cycle, and distinguishes resistance that is already present before treatment from resistance that evolves under therapeutic pressure. We then examine biomarkers that attempt to anticipate resistance, including PD-L1 expression, mismatch-repair status, tumor mutational burden, interferon-gamma signatures, HLA genotype and spatial immune architecture, and discuss why no single marker is sufficient. Strategies to overcome resistance are surveyed, from neoadjuvant timing and rational drug combinations to cellular therapy, personalized vaccines and microbiome modulation, together with the clinical evidence supporting or limiting each. Finally, we outline translational obstacles, including trial design, heterogeneity, and the need for dynamic biomarkers, and propose directions for future work. A mechanism-guided, biomarker-driven approach is likely to be required to extend the benefit of immunotherapy to a larger proportion of patients.