Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types. Tumor-associated macrophages (TAMs) play a key role in promoting tumor malignant progression and therapy resistance. However, the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic. This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo. TAMs have been found to suppress cervical cancer cells ferroptosis. Mechanistically, macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells. In cancer cells, miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis. Moreover, the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway. Importantly, in clinical cervical cancer cases, ALOX15 is negatively associated with macrophages infiltration, which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer. Moreover, both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer. Altogether, this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.

诱导癌细胞铁死亡已被提议作为几种癌症类型的潜在治疗方法。肿瘤相关巨噬细胞（TAM）在促进肿瘤恶性进展和治疗耐药中发挥关键作用。然而，TAM 在调节肿瘤铁死亡中的作用和机制仍未被探索，并且仍然是个谜。这项研究表明铁死亡诱导剂在体外和体内对宫颈癌具有治疗效果。TAM 被发现可以抑制宫颈癌细胞铁死亡。从机制上讲，包装到外泌体中的巨噬细胞衍生的 miRNA-660-5p 被转运到癌细胞中。在癌细胞中，miRNA-660-5p 减弱 ALOX15 表达以抑制铁死亡。此外，巨噬细胞中miRNA-660-5p的上调依赖于自分泌IL4/IL13激活的STAT6途径。重要的是，在临床宫颈癌病例中，ALOX15与巨噬细胞浸润呈负相关，这也提出了巨噬细胞降低宫颈癌中ALOX15水平的可能性。此外，单变量和多变量 Cox 分析均显示 ALOX15 表达是独立的预后因素，与宫颈癌的良好预后呈正相关。共，