Decoding signaling architectures: CAR versus TCR dynamics in solid tumor immunotherapy

The T cell receptor (TCR) initiates signaling by specifically recognizing peptide-MHC complexes, triggering the phosphorylation of CD3 chain immunoreceptor tyrosine-based activation motifs (ITAMs). This recruits kinases such as ZAP70, triggering a tightly regulated signaling cascade that governs T cell activation, differentiation, and effector functions. In contrast, the chimeric antigen receptor (CAR) is a synthetic construct that bypasses MHC restriction by fusing an antigen-binding domain with intracellular signaling modules (usually CD3ζ and co-stimulatory domains) from the TCR complex and other receptors. CAR-T cell therapy has revolutionized the treatment of hematologic malignancies, resulting in durable remission of B-cell leukemia, lymphoma, and multiple myeloma. However, its efficacy in solid tumors is limited by intrinsic barriers: poor CAR-T-cell trafficking/infiltration into tumors, the immunosuppressive tumor microenvironment (TME), intratumoral metabolic competition, and tumor antigen heterogeneity/loss. To improve CAR-T-cell function in solid tumors, numerous studies have explored multiple strategies: engineering CARs to boost immune synapse formation via optimized receptor clustering, increasing the ITAM number/strength to amplify downstream signaling, and incorporating novel/multiple co-stimulatory domains to sustain T-cell activation and persistence. Additionally, approaches include the use of CAR-T cells that secrete pro-inflammatory cytokines, epigenetic reprogramming to preserve T-cell stemness and functionality, and the use of synthetic biology tools for tunable/logic-gated CAR activation. Here, we summarize the current understanding of CAR signaling dynamics and highlight recent breakthrough strategies designed to overcome these challenges in solid tumors. These advances narrow the liquid-solid tumor efficacy gap, holding promise for better clinical outcomes in patients with solid malignancies and a new era of personalized immunotherapy.