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

Photodynamic therapy (PDT) provides non-invasive precision for superficial lesions but achieves suboptimal responses in hypoxic tumors such as head and neck squamous cell carcinoma (HNSCC). Spatially heterogeneous resistance mechanisms pose a major translational constraint for extending PDT applicability. To overcome this limitation, actionable targets were mapped within tumor spatial heterogeneity, circumventing conventional nanomaterial-based hypoxia-reversal strategies with inherent design complexity and protracted translation timelines. Spatial transcriptomic profiling of HNSCC specimens revealed pronounced molecular gradients along hypoxic regions, pinpointing <i>IL1A</i> 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.