Endocrine-driven inflammatory-epigenetic adaptation as a proposed axis of radioresistance in endocrine-exposed prostate cancer: a translational hypothesis.

Radiotherapy response in prostate cancer is commonly interpreted through partly separate frameworks centered on androgen receptor (AR) signaling, DNA damage response (DDR), inflammatory adaptation, and lineage plasticity. Here, we propose a translational hypothesis particularly relevant to endocrine-exposed disease in settings of biologically meaningful endocrine exposure before or during radiotherapy, especially high-risk localized, locally advanced, and selected salvage settings: the radiosensitizing effect of AR suppression may be temporally dynamic rather than fixed. In a subset of tumors, sustained endocrine pressure may initially impair AR-dependent DDR signaling but subsequently promote adaptive inflammatory signaling and epigenetic remodeling that attenuate this benefit and favor relative radioresistance. We propose a sequence-level model in which endocrine therapy acts as the initiating biologic stressor, inflammatory signaling functions as the adaptive amplifier, and epigenetic remodeling stabilizes a more durable treatment-tolerant state that becomes functionally revealed in the radiotherapy setting. While several bilateral links within this framework are supported by existing literature, the full temporally ordered cascade should be regarded as inferential and hypothesis-generating. The novelty of this framework lies not in proposing a new pathway, but in reframing endocrine-associated radiosensitization as a dynamic biologic state that may diverge over time across apparently similar treatment paradigms. This model yields clear translational predictions: endocrine-exposed tumors should differ in their propensity to develop adaptive inflammatory activation, inflammatory-high states should show attenuated radiosensitization and more repair-supportive features, and serial biomarker profiling across endocrine exposure and radiotherapy should outperform baseline-only assessment for identifying emerging resistance.