Zhou Zhe, Zhang Xu, Zhu Susi, Liu Waner, Guo Yeye, Xiong Siyu, Peng Cong, Chen Xiang
The Department of Dermatology Xiangya Hospital Central South University Changsha China.
Furong Laboratory Changsha China.
MedComm (2020). 2025 Jul 21;6(8):e70286. doi: 10.1002/mco2.70286. eCollection 2025 Aug.
Lactate is a vital metabolite in cancer, significantly impacting tumor progression, metastasis, and overall survival. The CD147-monocarboxylate transporter 1 (MCT1) complex, a major lactate transporter, has emerged as a promising therapeutic target. However, no effective protein-protein interaction (PPI) inhibitors targeting the CD147-MCT1 complex have been identified. In this study, we found that the small-molecule inhibitor crizotinib effectively disrupts the CD147-MCT1 interaction, leading to reduced lactate secretion from melanoma cells and decreased lactate uptake by macrophages. In vivo studies demonstrated that crizotinib treatment significantly suppressed tumor growth and enhanced responsiveness to immune checkpoint blockade therapy. Flow cytometry revealed that this metabolic intervention inhibits M2 polarization and reshapes the tumor immune microenvironment. Transcriptomic analysis further revealed that lactate induces C-X-C motif chemokine ligand 13 (CXCL13) expression in macrophages, which enhances melanoma invasiveness and impairs immune cell-mediated cytotoxicity. Importantly, crizotinib suppresses CXCL13 expression by blocking lactate-driven histone lactylation, thereby reversing the transcriptional reprogramming induced by lactate, as evidenced by reduced histone H3 lysine 18 lactylation (H3K18la) enrichment at the CXCL13 promoter. Taken together, these findings provide new insights into targeting metabolic-immune crosstalk and highlight the value of disrupting CD147-MCT1 interactions to improve immunotherapeutic responses in patients with melanoma.
乳酸是癌症中的一种重要代谢产物，对肿瘤进展、转移和总体生存有显著影响。CD147-单羧酸转运蛋白1（MCT1）复合物作为主要的乳酸转运体，已成为一个有前景的治疗靶点。然而，尚未发现针对CD147-MCT1复合物的有效蛋白质-蛋白质相互作用（PPI）抑制剂。在本研究中，我们发现小分子抑制剂克唑替尼可有效破坏CD147-MCT1的相互作用，导致黑色素瘤细胞乳酸分泌减少以及巨噬细胞乳酸摄取降低。体内研究表明，克唑替尼治疗可显著抑制肿瘤生长，并增强对免疫检查点阻断疗法的反应性。流式细胞术显示，这种代谢干预可抑制M2极化并重塑肿瘤免疫微环境。转录组分析进一步揭示，乳酸可诱导巨噬细胞中C-X-C基序趋化因子配体13（CXCL13）的表达，这会增强黑色素瘤的侵袭性并损害免疫细胞介导的细胞毒性。重要的是，克唑替尼通过阻断乳酸驱动的组蛋白乳酸化来抑制CXCL13的表达，从而逆转乳酸诱导的转录重编程，CXCL13启动子处组蛋白H3赖氨酸18乳酸化（H3K18la）富集减少证明了这一点。综上所述，这些发现为靶向代谢-免疫串扰提供了新见解，并突出了破坏CD147-MCT1相互作用以改善黑色素瘤患者免疫治疗反应的价值。
