Targeting IL-1α Sensitizes HNSCC to PDT by Reversing Hypoxia and NF-κB-Driven Oxidative Stress Resistance

as the most significantly upregulated transcript in hypoxic niches, which directly correlates with adverse clinical outcomes. PDT further amplified IL-1α expression, establishing a self-reinforcing resistance loop. Functional analyses confirmed that hypoxic tumor-derived IL-1α activates the NF-κB pathway to confer resistance against PDT-induced oxidative stress. Critically, the selective IL-1R1 antagonist AF12198 disrupted this resistance axis, significantly enhancing PDT efficacy across cellular models and patient-derived organoids (PDOs). Pharmacological blockade of the IL-1α/IL-1R1/NF-κB axis represents a clinically actionable strategy against intrinsic PDT resistance. By leveraging spatial heterogeneity to identify IL-1α as a druggable target, this study provides robust preclinical support for repurposing clinical IL-1 inhibitors to enhance PDT efficacy.