Radiotherapy, including brachytherapy, is a major therapeutic regimen for cervical cancer. Radioresistance is a decisive factor in radiation treatment failure. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critical factors in the curative effects of cancer therapies. However, the interactions between TAMs and CAFs in the context of ionizing radiation are not fully understood. This study was undertaken to investigate whether M2 macrophages induce radioresistance in cervical cancer and to explore the TAMs’ phenotypic transformation after IR and its underlying mechanisms. The radioresistance of cervical cancer cells was enhanced after being co-cultured with M2 macrophages. TAMs tended to undergo M2 polarization after high-dose irradiation, which was strongly associated with CAFs in both mouse models and patients with cervical cancer. Additionally, cytokine and chemokine analysis was performed to find that high-dose irradiated CAFs promoted macrophage polarization towards the M2 phenotype through chemokine (C-C motif) ligand 2. Collectively, our results highlight the crucial role that high-dose irradiated CAFs play in the regulation of M2 phenotype polarization, which ultimately induces radioresistance in cervical cancer.

Platinum resistance remains a major obstacle in ovarian cancer, yet whether abnormal glycolysis and lactate metabolism drive this phenotype through protein lactylation remains unclear. Here, we investigated the role of lactate-driven protein lactylation in platinum resistance and sought to identify the key effector event involved. Global protein lactylation was assessed by immunohistochemistry in tumor samples from 122 patients with high-grade serous ovarian cancer, and integrated proteomic and lactylomic analyses were performed in fresh frozen tumors from 12 patients, followed by validation in ovarian cancer cell models and functional assays. Platinum resistant ovarian cancer exhibited enhanced glycolysis, increased lactate accumulation, and elevated global protein lactylation, which was associated with platinum resistance and shorter progression free survival. Integrated lactylome profiling identified ZMYM2 K529 lactylation as a platinum resistance associated event, and ZMYM2 was upregulated in platinum resistant tissues and cells. Mechanistically, lactate promoted ZMYM2 K529 lactylation, suppressed ubiquitin–proteasome mediated degradation, and increased ZMYM2 stability and abundance. Functionally, ZMYM2 enhanced cisplatin tolerance, homologous recombination repair, and tolerance to DNA damaging treatments. However, both wild-type ZMYM2 and the K529R mutant restored platinum-resistant phenotypes in ZMYM2-knockdown cells, indicating that K529 lactylation primarily maintains ZMYM2 stability rather than directly determining its downstream pro-resistance activity. Collectively, these findings identify a glycolysis–lactate–ZMYM2 lactylation axis that promotes platinum resistance in ovarian cancer and highlight lactylation-dependent ZMYM2 stabilization as a potential therapeutic vulnerability.