Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1.

ABSTRACT

BACKGROUND: Great progress has been made in applying immunotherapy to the clinical treatment of tumors. However, many patients with triple-negative breast cancer (TNBC) cannot benefit from immunotherapy due to the immune desert type of TNBC, which is unresponsive to immunotherapy. DMKG, a cell-permeable derivative of α-KG, has shown potential to address this issue. METHOD: We investigated the effects of combining DMKG with radioimmunotherapy on TNBC. We assessed the ability of DMKG to promote tumor cell apoptosis and immunogenic death induced by radiotherapy (RT), as well as its impact on autophagy reduction, antigen and inflammatory factor release, DC cell activation, and infiltration of immune cells in the tumor area. RESULT: Our findings indicated that DMKG significantly promoted tumor cell apoptosis and immunogenic death induced by RT. DMKG also significantly reduced autophagy in tumor cells, resulting in increased release of antigens and inflammatory factors, thereby activating DC cells. Furthermore, DMKG promoted infiltration of CD8 + T cells in the tumor area and reduced the composition of T-regulatory cells after RT, reshaping the tumor immune microenvironment. Both DMKG and RT increased the expression of PD-L1 at immune checkpoints. When combined with anti-PD-L1 drugs (α-PD-L1), they significantly inhibited tumor growth without causing obvious side effects during treatment. CONCLUSION: Our study underscores the potential of pairing DMKG with radioimmunotherapy as an effective strategy for treating TNBC by promoting apoptosis, immunogenic death, and remodeling the tumor immune microenvironment. This combination therapy could offer a promising therapeutic avenue for TNBC patients unresponsive to conventional immunotherapy.