Combination of External Beam Radiation Therapy and Immune Checkpoint Inhibitors in Cancer Treatment: Mechanisms, Limitations, and Clinical Applications

Abstract External beam radiation therapy (EBRT) has long been integral in cancer treatment, effectively targeting localized and metastatic tumors. Immunotherapy, especially immune checkpoint inhibitors (ICIs), leverages the immune system to eliminate cancer cells but faces challenges such as treatment resistance. EBRT may provide an approach to overcoming resistance to ICI therapy, thus enhancing ICIs’ efficacy and broadening their clinical scope. EBRT, by inducing immunogenic cell death, primes the immune system and can potentiate ICIs. This combination strategy has shown promise in preclinical studies, highlighting the potential of EBRT to overcome the limitations of ICI monotherapy and vice versa. Clinical trials have demonstrated the safety and feasibility of this combination, with evidence suggesting improved tumor control and patient outcomes. Nevertheless, numerous challenges remain. This review explores the mechanisms, challenges, and clinical trials evaluating the combination of EBRT and ICIs, underscoring the need for optimized approaches to maximize clinical efficacy, while minimizing toxicities.