Abstract- Cardiothoracic malignancies such as lung and esophageal cancer are among the most dif-ficult-to-treat malignancies, being highly lethal with aggressive clinical behaviors. Im-munotherapy has become the game-changing method, capitalizing on the natural immune machinery for augmenting the anti-tumor response. Along with considerable successes in the clinical setting, drug resistance, selection of patients through biomarkers, and han-dling toxicities continue to be principal stumbling blocks to optimal therapeutic manage-ment. This review offers an extensive overview of recent developments in immunother-apy of cardiothoracic malignancies, such as immune checkpoint inhibitors (ICIs), cellu-lar therapy, cancer vaccines, and viral-based immunotherapies. We also discuss novel biomarkers, artificial intelligence (AI)-based predictive models, and combination ap-proaches to prevent resistance and maximize efficacy. A comprehensive review of peer-reviewed clinical trials, real-world evidence, and translational studies was performed with a focus on new immunotherapeutic strategies and their clinical significance. Special attention was given to biomarker identification, AI-based treatment choice, and novel combination regimens. The combination of biomarker-guided immunotherapy, predictive modeling with AI, and multimodal treatment modalities has dramatically enhanced pa-tient stratification and rates of therapeutic response. Although PD-1/PD-L1 and CTLA-4 inhibitors continue to be the bedrock of immunotherapy, new approaches like T-cell en-gineering, oncolytic viruses, and targeted cancer vaccines are demonstrating promising activity in preclinical and clinical environments. In addition, combination treatments, such as ICIs with chemotherapy, targeted therapy, and radiation, have shown increased efficacy in overcoming resistance. Nonetheless, issues like immune-related toxicities, treatment availability, and cost remain.
