KIRA6 restrains the generation of myeloid-derived suppressor cells and overcomes resistance to anti-PD-1 therapy.

Immune checkpoint blockade (ICB) therapy is one of the cornerstones of cancer treatment regimens, but the overall response rates remain low because of suppressive immune cells, such as myeloid-derived suppressor cells (MDSC). Therefore, it is unmet need to target MDSC to achieve better outcomes of ICB therapy. Inositol-requiring enzyme 1α (IRE1α) is identified as a key regulator for the generation of MDSC. Here, we evaluated the potential of KIRA6, an inhibitor for IREα kinase activity and RNase activity, to abrogate MDSC-mediated immune suppression. KIRA6 significantly suppressed 4T1 tumor growth, decreased MDSC population and enhanced T cell infiltration. Two dosages of KIRA6 treatment directly inhibited extramedullary myelopoiesis and MDSC generation in vivo. KIRA6 abrogated the induction of MDSC from bone marrow cells and abolished the immunosuppressive capability of MDSC in vitro. Meanwhile, KIRA6 not only attenuated G-CSF production from tumor cells thereby blocking the induction of MDSC, but also caused apoptosis of tumor cells. Moreover, KIRA6 treatment diminished MDSC generation, restored T cell proportion in both local and systemic immune landscapes and eventually overcame resistance to anti-PD-1 therapy. Our work establishes the evidence for KIRA6 as an impressive agent for abrogating MDSC-mediated immune suppression, killing tumor, and overcoming ICB resistance.