Natural products in lymphoma therapy: Integrating mechanisms, tumor microenvironment modulation, and translational challenges.

Abstract

Lymphoma is a heterogeneous group of malignant neoplasms originating from the lymphohematopoietic system, with relapse, drug resistance, and treatment-related toxicity remaining major clinical challenges. Owing to their structural diversity, capacity to modulate multiple signaling nodes, and potential to reshape the tumor immune microenvironment, natural products have emerged as a promising source for anti-lymphoma drug development and for sensitizing combination regimens. This review summarizes the pharmacological activities, mechanisms of action, preclinical evidence, and translational limitations of flavonoids, quinones, polyphenols, alkaloids, terpenoids, saponins, and polysaccharides. Key signaling cascades and the tumor immune microenvironment are additionally incorporated. However, translational potential is substantially limited by insufficient in vivo exposure, a disconnect between pharmacokinetics and pharmacodynamics (PK/PD), limited selectivity of pro-oxidant effects, a narrow therapeutic window, structural heterogeneity, and a lack of standardized formulations. Collectively, current evidence suggests that natural products should be repositioned from empirically derived cytotoxic candidates to mechanism-guided adjunctive agents for combination therapy in lymphoma. Future studies should further integrate PK/PD relationships, lymphoma molecular subtypes, tumor immune microenvironment status, and standardized formulation evaluation to better define their indications and translational boundaries.