Next-Generation CAR-T Combinations: Integrating Nanomedicine, Metabolic Reprogramming, and AI for Solid Tumor Targeting

Background Chimeric Antigen Receptor (CAR)-T cell therapy has demonstrated remarkable clinical success in hematological malignancies; however, its translation to solid tumors remains limited due to the hostile tumor microenvironment (TME), characterized by physical barriers, immunosuppression, metabolic competition, and treatment-limiting toxicities such as Cytokine Release Syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Purpose This review aims to critically evaluate next-generation combination strategies that enhance CAR-T efficacy in solid tumors, with particular emphasis on phytochemicals and natural small molecules as immunometabolic modulators within multimodal therapeutic frameworks. Study Design This is a narrative and mechanism-oriented review integrating evidence from immunotherapy, pharmacology, nanomedicine, and computational biology. Methods Relevant literature was systematically examined to analyze emerging approaches that combine CAR-T therapy with nanotechnology-enabled delivery systems, phytochemical-based metabolic modulation, and artificial intelligence-driven network pharmacology. Mechanistic pathways including AMPK-mTOR-SIRT1 signaling, NF-κB activation, STAT3 signaling, and NLRP3 inflammasome regulation were evaluated in the context of CAR-T persistence, metabolic fitness, and toxicity mitigation. Results Evidence indicates that localized nanotechnology platforms such as “backpack” nanoparticles improve CAR-T trafficking and reduce systemic toxicity. Phytochemicals including resveratrol, berberine, curcumin, and baicalin function as metabolic regulators that promote mitochondrial fitness, shift T-cell metabolism toward oxidative phosphorylation, and attenuate hyperinflammatory signaling underlying CRS. Artificial intelligence and network pharmacology approaches further enable rational identification of synergistic combinations and predictive responder stratification. Conclusion Multimodal precision strategies integrating nanotechnology, phytochemical immunometabolic modulation, and computational design represent promising avenues to overcome solid tumor resistance to CAR-T therapy. Repositioning natural small molecules as mechanistic immunopharmacological adjuvants may enhance therapeutic durability while reducing toxicity, supporting their translational potential in solid tumor immunotherapy.