Targeting peptide-HLA complexes for precision immunotherapy

Precision immunotherapy leverages the immune system to selectively eliminate abnormal cells while sparing healthy cells. Targeting specific peptide-human leukocyte antigen (pHLA) complexes, derived from cancer, autoimmune, and infectious disease, enables precise intervention, because these antigens are minimally expressed in normal tissues. However, designing binders with high specificity and low cross-reactivity remains challenging. Inspired by natural T cell receptor (TCR) recognition of pHLA complexes, synthetic approaches, including TCR-mimic antibodies (TCRm) and de novo pHLA binders, are emerging, adaptable into T cell engagers and adoptive therapies with promising specificity and efficacy. Moreover, advances in artificial intelligence (AI)-driven methods, immunopeptidomics, and computational protein design are accelerating the discovery and pan-allelic development of highly specific pHLA therapeutics. In this review, we discuss current approaches, mechanisms, preclinical and clinical data, and cutting-edge technologies shaping the future of pHLA-targeted immunotherapies.