Mechanistic Links Between Natural Bioactive Molecules and Tumor Immune Microenvironment States in PD-1/PD-L1 Resistance.

Programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) blockade can produce durable responses, but primary and acquired resistance are common. Treatment outcome is influenced by antigen presentation, T-cell localization, suppressive myeloid populations, metabolic stress, and the gut microbiome, all of which shape the tumor immune microenvironment (TIME). This review examines natural bioactive molecules in relation to these resistance features rather than grouping them by chemical class. Castalagin/camu-camu, ginseng polysaccharides, and ginsenoside Rh2 have the clearest preclinical evidence from direct PD-1/PD-L1-combination studies; evidence for the curcumin-gasdermin E (GSDME) axis comes from one recent study. Demethylzeylasteral has a well-supported ubiquitin-specific peptidase 22 (USP22)-PD-L1 degradation mechanism, but the reported antibody combination used cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) rather than PD-1/PD-L1. ACT001, berberine, baicalein, and several other candidates are supported mainly by indirect evidence of PD-L1 regulation or TIME remodeling. The translational value of these findings depends on exposure, target engagement, model selection, biomarker design, and material quality. Relating each candidate to a defined resistance setting helps distinguish promising combinations from mechanistic leads that still require direct testing.