Emerging target antigen landscape for CAR T-cell therapy in solid tumors: current advances and future directions

Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable clinical success in hematologic malignancies but remains largely ineffective in solid tumors due to antigen heterogeneity, immune evasion, and dose-limiting toxicities. A central challenge is the identification of optimal target antigens that balance tumor specificity with therapeutic efficacy. In this review, we define the emerging antigenic landscape for CAR T-cell therapy in solid tumors through integrative curation and systems-level analysis. We reviewed 58 candidate targets spanning tumor-associated surface molecules, stromal and angiogenic components, immune checkpoints, and regulatory signaling nodes. Pathway enrichment reveals convergence on key oncogenic and immune regulatory circuits, including cell adhesion, receptor tyrosine kinase signaling, and PD-1/PD-L1 mediated immune suppression, underscoring their roles in tumor progression and immune escape. Notably, most prioritized targets localize to the plasma membrane and cell-cell interfaces, reinforcing their accessibility for CAR-based interventions. We further highlight advances in multi-antigen targeting, logic-gated CAR designs, and engineered resistance to immunosuppressive cues that collectively address tumor heterogeneity and functional exhaustion. By integrating antigen biology with emerging engineering strategies, this review provides a conceptual framework for rational target selection and combinatorial design. These insights advance the development of next-generation CAR T-cell therapies with improved precision and durability against solid tumors.