Abstract
Breast cancer (BCa) is the second most diagnosed malignancy among women worldwide and is commonly treated with breast-conserving surgery (BCS) followed by radiotherapy (RT), such as targeted intraoperative radiotherapy (TARGIT-IORT). TARGIT-IORT delivers a single high dose to the tumor bed during surgery, providing local control while minimizing exposure to the surrounding tissues. However, the clinical role of IORT has become highly contested. The adoption of ultrashort external beam schedules eliminates many of its practical advantages, and the 2024 ASTRO guideline no longer recommends IORT outside clinical trials or registries. This narrative review summarizes evidence on the immunological and biological modulation of the tumor microenvironment (TME) by TARGIT-IORT/IORT, highlighting effects on cytokine profiles and wound healing dynamics. Rather than proposing routine clinical use, the review frames IORT as a translational model to study perioperative immunomodulation in breast cancer. Analyses of surgical wound fluid, immune biomarkers, and microRNA (miR) expression indicate that TARGIT-IORT/IORT disrupts tumor-supportive wound healing and reshapes local immune signaling. Early trial data suggested non-inferior outcomes compared with external beam radiation, but other studies reported higher recurrence risks. These divergent results, together with the availability of FAST-Forward external beam radiotherapy (EBRT), have limited IORT's relevance for standard care. Variability in immune findings underscores the need for standardized biomarker assessment protocols and supports positioning IORT as a research platform rather than a clinical replacement. Future studies should evaluate immune-modulating strategies alongside TARGIT-IORT within prospective trials, refine perioperative biomarker profiling, and integrate these findings with broader immuno-oncology approaches. Although not guideline-endorsed for routine treatment, IORT remains valuable as a translational tool for investigating perioperative tumor-immune interactions in breast cancer.