Understanding cardiac toxicity and immune responses to thoracic radiation therapy in non-small cell lung cancer - implications for future research.

Thoracic radiation therapy (RT) remains a mainstay treatment for locally advanced non-small cell lung cancer (NSCLC). However, recent evidence highlights significant long-term toxicities to the cardiac and immune systems, with implications for overall survival. This perspective review article examines the impact of thoracic RT on cardiac substructures and their detrimental correlation with survival. We recognized a discrepancy between major adverse cardiac events and overall survival and formulated an intriguing hypothesis linking thoracic RT to immunosuppression. Radiation to lymphocyte-rich tissues and circulating immune cells may induce profound lymphopenia, compromise immune surveillance, and reduce the efficacy of immunotherapy. We propose a dynamic exchange model between circulating lymphocytes and tumor-infiltrating lymphocytes in the context of thoracic RT and systemic immunotherapy. Herein, we highlight the importance of preserving immune system integrity and incorporating promising immune-sparing techniques in radiation planning. In summary, thoracic RT should be re-envisioned not only as an ablative local therapy, but also as a systemic immune modulator in the management of NSCLC.