Type‐I protein arginine methyltransferase inhibition primes anti‐programmed cell death protein 1 immunotherapy in triple‐negative breast cancer

Abstract Background Immune‐checkpoint blockade (ICB) therapy shows promise for treating aggressive triple‐negative breast cancer (TNBC). However, only some patients benefit from ICB, revealing an urgent need for identifying novel strategies for sensitizing patients to ICB. Previously, the authors demonstrated that type‐I protein arginine methyltransferases (PRMTs) regulated antiviral innate‐immune responses in TNBC by altering RNA splicing. This study aimed to explore the effects of targeting type‐I PRMTs on the tumor microenvironment (TME) and the efficacy of ICB therapy against TNBC. Methods Single‐cell transcriptomic analysis was performed to investigate the effects of type‐I PRMT inhibition on the TME, especially T‐cell subsets. Single‐cell T‐cell receptor sequencing was performed to analyze the diversity and dynamics of the T‐cell repertoire. A syngeneic murine model of TNBC was used to evaluate the therapeutic efficacy and immune memory effect of combining a type‐I PRMT inhibitor (MS023) with an anti‐programmed cell death protein 1 (PD‐1) antibody. Results Type‐I PRMT inhibition combined with anti–PD‐1 therapy reduced tumor growth. Mechanistically, type‐I PRMT inhibition reshaped the TME. Increased CD8 T‐cell infiltration was verified using flow cytometry. Increased clonotypes and clonal diversity were also observed after MS023 treatment, which contributed to immune memory following combination treatment. Conclusions Targeting type‐I PRMT can potentially improve immunotherapeutic efficacies in patients with TNBC. By enhancing the tumor immunogenicity and promoting a more favorable immune microenvironment, this combined approach may enable more patients with TNBC to benefit from immunotherapies.