The polarization of tumor-associated macrophages (TAMs) from M2 to M1 phenotype demonstrates great potential for remodeling the immunosuppressive tumor microenvironment (TME) of hepatocellular carcinoma (HCC). d -lactate (DL; a gut microbiome metabolite) acts as an endogenous immunomodulatory agent that enhances Kupffer cells for clearance of pathogens. In this study, the potential of DL for transformation of M2 TAMs to M1 was confirmed, and the mechanisms underlying such polarization were mainly due to the modulation of phosphatidylinositol 3-kinase/protein kinase B pathway. A poly(lactide- co -glycolide) nanoparticle (NP) was used to load DL, and the DL-loaded NP was modified with HCC membrane and M2 macrophage-binding peptide (M2pep), forming a nanoformulation (DL@NP-M-M2pep). DL@NP-M-M2pep transformed M2 TAMs to M1 and remodeled the immunosuppressive TME in HCC mice, promoting the efficacy of anti-CD47 antibody for long-term animal survival. These findings reveal a potential TAM modulatory function of DL and provide a combinatorial strategy for HCC immunotherapy.

中文翻译：

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d-乳酸调节 M2 肿瘤相关巨噬细胞并重塑肝细胞癌的免疫抑制肿瘤微环境

肿瘤相关巨噬细胞 (TAM) 从 M2 表型到 M1 表型的极化表明在重塑肝细胞癌 (HCC) 的免疫抑制肿瘤微环境 (TME) 方面具有巨大潜力。d-乳酸（DL；一种肠道微生物代谢物）作为内源性免疫调节剂，增强库普弗细胞清除病原体的能力。本研究证实了DL将M2 TAM转化为M1的潜力，这种极化的机制主要是由于磷脂酰肌醇3激酶/蛋白激酶B途径的调节。聚(丙交酯-共使用HCC膜和M2巨噬细胞结合肽（M2pep）对负载DL的纳米粒子（NP）进行修饰，形成纳米制剂（DL@NP-M-M2pep）。DL@NP-M-M2pep 将 M2 TAM 转化为 M1，并重塑了 HCC 小鼠中的免疫抑制 TME，提高了抗 CD47 抗体对动物长期生存的功效。这些发现揭示了 DL 的潜在 TAM 调节功能，并为 HCC 免疫治疗提供了组合策略。