Low-dose taxanes induce γδ-T cell reprogramming and ANXA6/PPP2R1A release to synergistically treat triple-negative breast cancer

Abstract Taxanes play pivotal roles across therapeutic stages of triple-negative breast cancer (TNBC), yet their efficacy is substantially limited by drug resistance and systemic toxicity. Immunotherapy has been found to enhance the efficacy of chemotherapy. Here, we investigated the synergistic antitumor activity between taxanes and γδ-T cells, a major histocompatibility complex-independent T cell subset with potent cytotoxic activity against tumor cells. Interestingly, low-dose taxanes suppressed tumor cell proliferation while concurrently promoting γδ-T cell growth and effector function. Furthermore, low-dose taxanes and γδ-T cells synergistically controlled TNBC both in vitro and in vivo. Through transcriptomic analysis followed by functional validation, taxanes were shown to induce γδ-T cells to release ANXA6 and PPP2R1A. Notably, high expression of these two proteins was associated with an improved prognosis in patients with breast cancer. More interestingly, low-dose taxanes and γδ-T cells also showed synergistic effects against multiple chemoresistant TNBC models. In these models, γδ-T cells effectively eradicated cancer stem-like cells. By integrating chemotherapy with γδ-T cell–mediated immunity, we introduce a novel therapeutic strategy that simultaneously improves treatment efficacy, overcomes resistance, and reduces toxicity—offering a promising advancement in TNBC management.