Molecular and Cellular TCR-Mimic Therapeutic Platforms for Cancer Therapy: A Comparative Review toward a...

T-cell receptor-mimic antibodies (TCRm-Abs) have enabled the specific targeting of peptide-major histocompatibility complexes (p-MHCs), thereby granting access to intracellular tumor antigens that are typically inaccessible to conventional antibody therapeutics. Nevertheless, the extremely low density of these complexes on the surface of tumor cells has remained the primary challenge for all TCRm-Ab-based platforms. This review provides a critical comparison of various molecular platforms-including TCRm-immunoconjugates (TCRm-ICs) and TCRm-bispecific T-cell engagers (TCRm BiTEs)-as well as cellular platforms, such as TCRm-chimeric antigen receptor (TCRm-CAR), antibody T-cell receptor (AbTCR), and Synthetic TCR and Antigen Receptor (STAR). It evaluates their design and optimization strategies to overcome low antigen density, mechanisms of action, translational potential, and current challenges. Immunoconjugates rely on payload potency and linker stability, engager molecules achieve serial killing through T cells, whereas cellular platforms-particularly STAR-attain antigen sensitivity comparable to that of native T-cell receptors by mimicking the TCRαβ architecture. Nonetheless, the durable clinical translation of these modalities remains limited. Based on these insights, we propose a context-driven selection framework that integrates molecular engineering, modulation of the tumor microenvironment, combination immunotherapy, and quantitative tumor characteristics to inform the preclinical development and rational selection of TCRm therapeutic platforms.