临床上使用的铂类化疗药物增加了肿瘤细胞产生M2巨噬细胞的能力，从而导致抗转移活性不佳和免疫抑制。溶酶体代谢对癌细胞迁移和侵袭非常关键，但它在抗肿瘤免疫和肿瘤细胞中的作用机制尚不清楚且尚不明确。本研究旨在利用固有代谢可塑性，探索一种相互协同的策略来破坏肿瘤的免疫抑制微环境，并发现金属药物。我们通过将生物碱性基团与顺铂配位来制备奈芙铂，以调节溶酶体功能。选取结直肠癌细胞进行体内生物学实验。通过流式细胞术分析，收集和分析了血液、肿瘤和脾脏组织，以进一步探索抗肿瘤活性与免疫细胞之间的关系。通过奈芙铂处理后确认了骨髓源性巨噬细胞（BMDM）和M2-BMDM向M1表型的转化。我们揭示了溶酶体介导的粘液磷脂酰肌苷1（Mcoln1）和有丝分裂原活化蛋白激酶（MAPK）在M2巨噬细胞极化中的关键机制。使用RNA测序（RNA-seq）进一步探索了高迁移群组1（HMGB1）介导的胶原酶L（CTSL）-溶酶体功能阻滞的关键机制。我们证明奈芙铂诱导了不同的溶酶体代谢程序，并重编程肿瘤细胞中的巨噬细胞来终止恶性肿瘤相关巨噬细胞（TAMs）-MDSCs-Treg三角关系。在机制上，奈芙铂处理后的巨噬细胞通过触发Mcoln1介导的Ca2+释放来引起溶酶体代谢的激活，从而诱导p38和核因子-κB（NF-κB）的激活，并最终导致M2巨噬细胞极化。相反，HMGB1介导的溶酶体代谢阻滞在癌细胞中与抗肿瘤效应强相关，通过促进HMGB1的胞质转位。本研究揭示了基于巨噬细胞的金属药物研究的关键策略，能够治疗免疫性“热”和“冷”型癌症。与传统的以DNA抑制为基础的铂类抗肿瘤药物不同，我们通过靶向溶酶体诱导巨噬细胞和肿瘤中的不同代谢程序，提供了一种强有力的抗肿瘤策略，用于癌症免疫治疗。© 2023年。意大利国家癌症研究所“Regina Elena”。

Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity.Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade.We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1.This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically "hot" and "cold" cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy.© 2023. Italian National Cancer Institute ‘Regina Elena’.