Immune Evasion and Resistance in Cancer Progression: Overcoming Checkpoint Inhibition Challenges with Personalized Immunotherapy Guided by PD-L1 Expression

Abstract

Immune evasion is a hallmark of cancer development and poses an important impediment to the effectiveness of immune checkpoint inhibitors (ICIs). Cancer cells take advantage of heterogeneous intrinsic and extrinsic pathways to circumvent immune detection, such as metabolic remodeling (e.g., increased glycolysis, activation of IDO1), genomic mutation (e.g., JAK/STAT, β-catenin), and epigenetic suppression of immune-regulatory genes. Concurrently, TME promotes immune suppression through Tregs, MDSCs, TAMs, and fibroblast-mediated extracellular matrix remodeling. Hypoxia and cytokine dysregulation also undermine antigen presentation and T-cell functionality. These immunoevasion strategies form the foundation of both native (innate) and adaptive resistance to ICIs, while recent evidence places emphasis on microbiota composition being able to modify therapeutic response. The PD-1/PD-L1 pathway remains the focus of ICI therapy, but PD-L1 expression is limited by spatial, temporal, and technical heterogeneity. Beyond PD-L1, integrated biomarker approaches including tumor mutational burden (TMB), microsatellite instability (MSI), IFN-γ gene signatures, and circulating tumor DNA (ctDNA) have arisen to further inform patient stratification. Emerging therapeutic technologies—e.g., dual checkpoint blockade, engineered cytokines, personalized neoantigen vaccines, and adoptive T cell therapy (CAR-T, TCR-T)—are designed to overcome resistance and maximize clinical efficacy. Integration of multi-omics and AI-based models provides additional precision in the tailoring of immunotherapy. This review integrates existing knowledge of immune escape and resistance, highlighting dynamic biomarker development and combinatorial approaches for next-generation personalized cancer immunotherapy.