Xu Chenchen, Chen Jiyu, Tan Mi, Tan Qingqing
Department of Gynecology and Obstetrics, Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
Front Immunol. 2025 Apr 22;16:1543096. doi: 10.3389/fimmu.2025.1543096. eCollection 2025.
Ovarian cancer (OC) remains the most lethal gynecological malignancy, primarily due to its late-stage diagnosis, frequent recurrence, and resistance to conventional chemotherapy. A critical factor contributing to OC's aggressiveness is the tumor microenvironment (TME), particularly the presence and polarization of tumor-associated macrophages (TAMs). TAMs, often skewed toward an immunosuppressive M2-like phenotype, facilitate tumor growth, angiogenesis, metastasis, and resistance to therapy. This comprehensive review delves into the multifaceted regulation of macrophage polarization in OC, highlighting key molecular pathways such as PTEN loss, Wnt/β-catenin signaling, NF-κB, Myc, STAT3, and JNK, among others. Additionally, it explores the role of chemokines, non-coding RNAs, and various proteins in modulating TAM phenotypes. Emerging evidence underscores the significance of extracellular vesicles (EVs) and ovarian cancer stem cells (CSCs) in promoting M2 polarization, thereby enhancing tumor progression and therapy resistance. The review also identifies critical biomarkers associated with macrophage polarization, including CD163, LILRB1, MUC2, and others, which hold prognostic and therapeutic potential. Therapeutic strategies targeting TAMs are extensively discussed, encompassing oncolytic viruses, engineered EVs, immunotherapies, nanoparticles, targeted therapies, and natural products. These approaches aim to reprogram TAMs from a pro-tumorigenic M2 state to an anti-tumorigenic M1 phenotype, thereby enhancing immune responses and overcoming resistance to treatments such as chemotherapy and immune checkpoint inhibitors. Furthermore, the review addresses the interplay between macrophage polarization and therapy resistance, emphasizing the need for novel interventions to modulate the TME effectively. By synthesizing current knowledge on macrophage polarization in ovarian cancer, this study underscores the potential of targeting TAMs to improve clinical outcomes and personalize treatment strategies for OC patients. Continued research in this domain is essential to develop robust therapeutic frameworks that can mitigate the immunosuppressive TME and enhance the efficacy of existing and novel cancer therapies.
卵巢癌（OC）仍然是最致命的妇科恶性肿瘤，主要原因是其晚期诊断、频繁复发以及对传统化疗的耐药性。促成OC侵袭性的一个关键因素是肿瘤微环境（TME），尤其是肿瘤相关巨噬细胞（TAM）的存在及其极化。TAM通常偏向免疫抑制性的M2样表型，促进肿瘤生长、血管生成、转移以及对治疗的耐药性。这篇综述深入探讨了OC中巨噬细胞极化的多方面调控，突出了关键分子途径，如PTEN缺失、Wnt/β-连环蛋白信号传导、NF-κB、Myc、STAT3和JNK等。此外，还探讨了趋化因子、非编码RNA和各种蛋白质在调节TAM表型中的作用。新出现的证据强调了细胞外囊泡（EV）和卵巢癌干细胞（CSC）在促进M2极化中的重要性，从而增强肿瘤进展和治疗耐药性。该综述还确定了与巨噬细胞极化相关的关键生物标志物，包括CD163、LILRB1、MUC2等，它们具有预后和治疗潜力。针对TAM的治疗策略得到了广泛讨论，包括溶瘤病毒、工程化EV、免疫疗法、纳米颗粒、靶向疗法和天然产物。这些方法旨在将TAM从促肿瘤的M2状态重编程为抗肿瘤的M1表型，从而增强免疫反应并克服对化疗和免疫检查点抑制剂等治疗的耐药性。此外，该综述还讨论了巨噬细胞极化与治疗耐药性之间的相互作用，强调了有效调节TME的新干预措施的必要性。通过综合目前关于卵巢癌中巨噬细胞极化的知识，本研究强调了靶向TAM以改善临床结果和为OC患者制定个性化治疗策略的潜力。在这一领域持续开展研究对于开发强大的治疗框架至关重要，这些框架可以减轻免疫抑制性TME并提高现有和新型癌症治疗的疗效。
