HER2 乳腺肿瘤具有丰富的免疫抑制细胞，包括 M2 型肿瘤相关巨噬细胞 (TAM)。尽管 TAM 由免疫刺激性 M1 型和免疫抑制性 M2 型组成，但免疫抑制性肿瘤中的 M1/M2-TAM 比率降低，导致其免疫治疗无效。 M1- 与 M2-TAM 的形成取决于精氨酸代谢的差异，其中 M1-TAM 将精氨酸转化为一氧化氮 (NO)，而 M2-TAM 将精氨酸转化为多胺 (PA)。我们假设 M1-TAM 与 M2-TAM 中如此不同的精氨酸代谢归因于 BH4（NO 合酶辅因子）的不同可用性，并且其补充会将 M2-TAM 重新编程为 M1-TAM。最近，我们报道了内源性 BH4 前体 Sepiapterin (SEP) 提高了 HER2 肿瘤内 M1-TAM 标记物的表达。在这里，我们发现 SEP 恢复了 M2 样巨噬细胞中的 BH4 水平，然后将精氨酸代谢重定向为 NO 合成，并将 M2 型转化为 M1 型。重编程的巨噬细胞表现出成熟的抗原呈递和诱导效应 T 细胞的能力，以触发 HER2 癌细胞的免疫原性细胞死亡。这项研究证实了 SEP 作为一种新型免疫治疗策略在 HER2 乳腺肿瘤微环境代谢转变中的效用。© 2024 Fernando 等人。

HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- versus M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.© 2024 Fernando et al.