AIM2 Lactylation Regulates Radiotherapy Sensitivity in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited targeted treatment options. Radiotherapy remains an important therapeutic approach for TNBC, but radioresistance markedly limits its efficacy. Absent in melanoma 2 (AIM2) has been increasingly implicated in tumor biology and innate immune signaling; however, its role in TNBC radioresistance and its regulation by the lactate-rich tumor microenvironment remain unclear.

Radiation-resistant TNBC cell models were established from BT-549 and MDA-MB-231 cells by repeated fractional irradiation. AIM2 knockdown and IRF3 overexpression were achieved by lentiviral transduction. Cell proliferation, colony formation, apoptosis, protein expression, AIM2 lactylation, subcellular localization, and AIM2-IRF3 interaction were evaluated using CCK-8 assay, colony formation assay, flow cytometry, RT-qPCR, Western blotting, co-immunoprecipitation, and immunofluorescence. Bioinformatics analyses were performed to assess the potential prognostic relevance of AIM2. In vitro experiments were performed with at least three independent biological replicates.

Radiation treatment increased AIM2 expression in TNBC cells. AIM2 knockdown reduced colony formation and promoted apoptosis in radioresistant TNBC cells. High-lactate conditions decreased AIM2 expression, increased AIM2 lactylation, and promoted AIM2 nuclear translocation. IRF3 overexpression partially reversed the effects of AIM2 knockdown on colony formation and apoptosis, whereas lactate treatment weakened the interaction between AIM2 and IRF3. Bioinformatics analyses indicated that elevated AIM2 expression was associated with poorer prognosis.

These findings suggest that AIM2 may be involved in the regulation of TNBC radioresistance, potentially through its interaction with IRF3. High-lactate conditions may affect this regulatory axis by enhancing AIM2 lactylation. This study provides preliminary evidence for a potential mechanism linking lactate-mediated post-translational modification with radiosensitivity regulation in TNBC; however, further mechanistic, in vivo, and clinical validation is required.