Immune checkpoint inhibitors and immunosuppressive tumor microenvironment: current challenges and strategies to overcome resistance

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review aims to explore the challenges posed by the immunosuppressive tumor microenvironment (TME) in response to immune checkpoint inhibitors (ICIs) and discusses potential strategies to overcome resistance. MATERIAL & METHODS: A comprehensive review of existing literature was conducted to analyze the immunosuppressive features of the TME, including the role of immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations, and overexpression of immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA). Additionally, strategies to overcome resistance-such as targeting immunosuppressive cells, normalizing tumor vasculature, dual or triple checkpoint blockade, and combining ICIs with vaccines, oncolytic viruses, and metabolic inhibitors-are elaborated. The need for predictive biomarkers to stratify patients and assess treatment response was also discussed. RESULTS: The review highlights that the immunosuppressive TME contributes significantly to resistance against ICIs, mediated through various mechanisms. Potential strategies to overcome resistance include modulating the TME by targeting immunosuppressive components, combination therapies, and the identification of predictive biomarkers. Further research and innovative approaches are required to fully understand TME-ICI interactions and change the face of cancer treatment.