Signaling Pathways as Drivers of Immunotherapy Resistance to Checkpoint Inhibitors (A Review)

Abstract Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by activating the immune system to attack tumors. However, many patients exhibit primary or acquired resistance, limiting their clinical benefit. Resistance to ICIs arises from tumor-intrinsic mechanisms, changes in the tumor microenvironment (TME), and immune cell dysfunction. Key signaling pathways, including PI3K/AKT/mTOR, Wnt/β-catenin, MAPK, JAK/STAT, and NF-κB, regulate tumor growth, immune evasion, and therapy response. Dysregulation of these pathways reduces antigen presentation, suppresses T-cell infiltration, and increases immune checkpoint expression. In the TME, hypoxia, TGF-β, VEGF, and immunosuppressive cells such as myeloid-derived suppressor cells and regulatory T cells foster resistance. Additionally, immune cell-intrinsic defects, including T-cell exhaustion and cytokine-mediated suppression, impede anti-tumor immunity. Literature reviewed includes studies addressing signaling networks, preclinical models, and early clinical trials targeting these mechanisms. Understanding resistance pathways is essential to improving ICI efficacy. Promising strategies include combination regimens targeting oncogenic signaling, epigenetic therapies, metabolic reprogramming, and immune-modulating agents. Advances in biomarker-driven stratification and personalized therapy are critical to extend immunotherapy benefits to more patients. Translating mechanistic insights into clinical practice will require integrated research efforts to overcome the multifactorial barriers to durable ICI responses.