Harnessing neoantigen-specific T cells for precision immunotherapy in hematologic malignancies

Antigen-specific T-cell immunotherapies are transforming the treatment landscape of hematologic malignancies. Neoantigen-specific therapies that exploit the ability of endogenous T-cell receptors (TCRs) to recognize tumor-derived peptides in an HLA-restricted context differ mechanistically from modalities employing chimeric antigen receptor T cells, which target surface antigens in an HLA-independent manner. In contrast to approaches targeting tumor-associated antigens, neoantigen-specific strategies offer more precise tumor selectivity and reduced off-target toxicity. Advances in immunogenomics, immunopeptidomics, and functional validation have accelerated the identification of both personalized and recurrent neoantigens, and high-resolution sequencing technologies have further facilitated the characterization of their cognate TCRs, which are currently being explored for developing TCR-engineered T-cell therapies. Early-phase clinical trials in hematologic malignancies demonstrate that neoantigen-specific strategies are safe and feasible across multiple hematologic cancers, with ongoing studies actively assessing the immunogenicity, clinical efficacy, and durability of these approaches. This review synthesizes recent preclinical and clinical advances in the discovery, validation, and therapeutic exploitation of neoantigen-specific strategies in blood cancers, highlighting translational insights for prioritizing immunogenic neoantigens. Emphasis is placed on identifying biological and technological barriers that limit the therapeutic efficacy of neoantigen-specific immunotherapies, with the goal of distilling actionable insights to guide their development in hematologic malignancies.