Liu Shuguang, Gong Hui, Li Peihang, Hu Jiahao, Li Yixuan, Xu Rou, Cai Junchao, Wang Shuqi, Cai Jiayi, Ma Hongmei, Mi Xirong, Li Yifan, Zhou Qingbo, Zhou Qiming, Yang Weiqiang, Li Riqing, Song Libing, Fang Lishan
Department of pathology, The Eighth Affiliated Hospital, Sun Yat-Sun University, Shenzhen, China.
Shenzhen Nanshan People's Hospital, Shenzhen, China.
Cell Death Dis. 2025 May 14;16(1):379. doi: 10.1038/s41419-025-07712-y.
Chemotherapy resistance in colorectal cancer (CRC) remains a major obstacle in clinical oncology. Analysis of clinical specimens from chemotherapy-resistant patients revealed elevated CXCL7 expression in tumor-associated macrophages (TAMs). Through integrated in vitro and in vivo studies, we demonstrated that chemotherapy induces tumor cell-macrophage crosstalk, leading to CXCL7 upregulation in TAMs. Using a co-culture system, we observed that CXCL7+ macrophages confer chemoresistance to CRC cells. Mechanistic investigations revealed that CXCL7 activates the CXCR2 receptor on tumor cells, triggering interferon signaling and promoting serine metabolism through STAT1-dependent transcriptional upregulation of phosphoglycerate dehydrogenase (PHGDH), the key enzyme in serine biosynthesis. This metabolic reprogramming enhances the paracrine secretion of S-adenosyl methionine (SAM), which drives chemotherapy resistance. Furthermore, CXCL7-mediated the paracrine secretion of SAM in tumor cells, which in turn promotes M2 macrophage polarization and sustains CXCL7 expression in TAMs. Our findings reveal that a CXCL7-SAM feedback loop between tumor cells and macrophages establishes a chemoresistant niche. This interaction represents a promising therapeutic target for overcoming chemoresistance in CRC.
结直肠癌（CRC）的化疗耐药性仍然是临床肿瘤学中的一个主要障碍。对化疗耐药患者的临床标本分析显示，肿瘤相关巨噬细胞（TAM）中CXCL7表达升高。通过综合的体外和体内研究，我们证明化疗诱导肿瘤细胞与巨噬细胞相互作用，导致TAM中CXCL7上调。使用共培养系统，我们观察到CXCL7+巨噬细胞赋予CRC细胞化疗耐药性。机制研究表明，CXCL7激活肿瘤细胞上的CXCR2受体，触发干扰素信号传导，并通过丝氨酸生物合成关键酶磷酸甘油酸脱氢酶（PHGDH）的STAT1依赖性转录上调促进丝氨酸代谢。这种代谢重编程增强了S-腺苷甲硫氨酸（SAM）的旁分泌分泌，从而导致化疗耐药。此外，CXCL7介导肿瘤细胞中SAM的旁分泌分泌，进而促进M2巨噬细胞极化并维持TAM中CXCL7的表达。我们的研究结果表明，肿瘤细胞与巨噬细胞之间的CXCL7-SAM反馈回路建立了一个化疗耐药微环境。这种相互作用代表了克服CRC化疗耐药性的一个有前景的治疗靶点。
