TCM-derived immunometabolic modulators as systems adjuvants for CAR-T therapy in solid tumors: evidence hierarchy and translational roadmap.

BACKGROUND

Solid-tumor CAR-T therapy remains limited by antigen heterogeneity, stromal exclusion, abnormal vasculature, immunosuppressive myeloid and fibroblast niches, hypoxia, nutrient competition, mitochondrial stress and inflammatory toxicity. These barriers indicate that solid-tumor CAR-T therapy is not only a receptor-engineering problem but also a systems pharmacology problem requiring rational combinatorial modulation.

MAIN BODY: This review evaluates whether traditional Chinese medicine (TCM)-derived formulations, botanical compounds and microbiota-derived natural-product metabolites can be developed as mechanism-defined adjuvants for solid-tumor CAR-T therapy. We classify evidence by proximity to CAR-T systems, but also emphasize that evidence ranking must be interpreted within specific use cases. Current evidence remains limited and predominantly preclinical, yet it supports testable intervention concepts involving purified ex vivo metabolic conditioning, in vivo tumor conditioning, concurrent maintenance, toxicity modulation and delivery engineering. We further propose a translational framework linking product identity, exposure window, target annotation, immune-functional potency, CAR-T manufacturing compatibility, pharmacodynamic biomarkers, host-model suitability, lymphodepletion compatibility and safety assessment.

CONCLUSION

TCM-derived agents should not be developed as empirical supplements for CAR-T therapy. Translation should require defined product identity, target clarity, use-case-specific evidence, exposure window matched to product class, CAR construct, tumor context, manufacturing compatibility, immune-functional potency testing, suitable immune models, lymphodepletion drug-interaction assessment, safety assessment and biomarker-rich early-phase trials with explicit go/no-go criteria.