Contextualizing Bioactive Natural Products at the Intersection of Checkpoint Inhibitor-related Cancer Immunotherapy and Pneumonitis Control

Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of lung cancer by restoring the anticancer immunity. However, their application is accompanied with an increasing incidence of immune-related adverse events, among which the checkpoint inhibitor-related pneumonitis (CIP) is the most serious. Current management of CIP using corticosteroids may compromise the anticancer effects, facing limitations and creating a fundamental therapeutic dilemma. Bioactive natural products have emerged as promising candidates to address this challenge. Methods This review aims to systematically profile the natural product candidates for CIP management. Firstly, current ICI regimes and the pathophysiological basis of CIP was retrospect, with highlighted limitations of current managements. Secondly, systematic review was performed to screening the emerging evidences supporting the use of natural products for protections against pneumonitis and ICI treatment enhancement. Finally, the advanced pharmaceutical formulations and inhalable delivery strategies were summarized for the inspiration of further studies and clinical translation. Results Totally 77 references were collected to profile the landscape of CIP management in lung cancer; about 143 references (including 102 original research studies) were retained to discuss the natural product effects in pneumonitis control and ICI enhancement; finally, 31 references were selected to show the advanced formulation (especially inhalable forms) that may improve pulmonary targeting and optimize therapeutic outcomes. Conclusion Taken together, natural products, particularly when combined with advanced formulation strategies, represent a promising avenue for simultaneously mitigating CIP and enhancing anti-tumour immunity, thereby improving the overall benefit-risk profile of cancer immunotherapy.