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

Abstract

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.

1. Introduction

Immunotherapy has emerged as a transformative approach in oncology, with T cell-based therapies at the forefront of innovation. Among these, CAR-engineered T cells and TCR-based therapies represent two powerful strategies that harness the immune system to target malignancies. While CAR-T cells have demonstrated remarkable success in hematologic cancers by recognizing surface antigens independent of presentation, their efficacy in solid tumors remains limited due to challenges such as immunosuppressive microenvironments, poor trafficking, and antigen heterogeneity. In contrast, TCR-based therapies leverage the natural precision of MHC-restricted antigen recognition, offering potential against intracellular targets but facing hurdles related to MHC downregulation and off-target toxicity.

Understanding the fundamental differences in signaling architecture between CAR and TCR is critical to optimizing T cell therapies for solid tumors. This review delves into the structural and functional divergence between these two systems, examines the role of various co-stimulatory domains in shaping CAR-T cell fate, and surveys current clinical trials and innovative strategies aimed at overcoming the barriers to effective solid tumor immunotherapy. By integrating insights from basic science and clinical advances, we aim to highlight pathways toward more durable and targeted immunotherapeutic interventions.