Harnessing Vδ1⁺ T cells for next-generation immunotherapy: from mechanistic insights to clinical translation

The unique ability of Vδ1⁺ T cells to recognize targets in a major histocompatibility complex (MHC)-unrestricted manner makes them promising candidates for immunotherapy. This review explores the biological underpinnings of their advantages, particularly their ability to penetrate and migrate through solid tumors, their antigenic promiscuity, and their functional plasticity in inflammatory tumor microenvironments. Based on this, we analyze the therapeutic pipeline derived from this biology, including targeted antibodies, bispecific molecules and a new generation of cellular products, among which chimeric antigen receptor (CAR)-engineered constructs have shown encouraging clinical responses. Nonetheless, translation into the clinic can often present challenges; we tackle the unresolved issues of product standardization, subset complexity, and microenvironmental suppression, offering practical ways forward. This review aims to serve as a reference to deepen the understanding of the anti-tumor value of Vδ1⁺ T cells and facilitate their translational development.