Mutant-Selective T-cell Receptor Therapy for Solid Tumors

Abstract Advanced solid tumors remain largely incurable, with most patients ultimately progressing despite modern therapies, including immune checkpoint blockade. The limited impact of these approaches reflects the biological complexity of solid tumors, including intratumoral heterogeneity, an immunosuppressive microenvironment, and the predominance of “undruggable” oncogenic drivers. Adoptive cellular therapy (ACT) offers a complementary strategy by delivering tumor-specific lymphocytes directly into patients. Among ACT modalities, T-cell receptor (TCR)–engineered T cells stand out for their ability to recognize intracellular neoantigens presented by major histocompatibility complex molecules, thus accessing a broader antigenic landscape. Early successes, such as the FDA approvals of lifileucel and afamitresgene autoleucel, highlight the promise of these approaches, whereas proof-of-concept clinical studies demonstrate the activity of personalized neoantigen-reactive TCRs in advanced solid tumors. Major challenges remain, including safety concerns from off-tumor toxicities and resistance mechanisms such as human leukocyte antigen loss of heterozygosity. Ongoing innovations in target discovery, TCR engineering, and combination strategies aim to overcome these barriers and establish mutant-selective TCR therapy as a viable therapeutic strategy in the treatment of solid tumors.