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Targeting IL-1α Sensitizes HNSCC to PDT by Reversing Hypoxia and NF-κB-Driven Oxidative Stress Resistance
Zhiyin Li1, Yikang Ji2, Xinran Zhao2
1Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology; Shanghai 200011, P.R. China.
Abstract:
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 IL1A 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.
Insights
Photodynamic therapy (PDT) shows limited efficacy in hypoxic tumors like HNSCC. Targeting the IL-1α pathway, identified through spatial transcriptomics, enhances PDT effectiveness by overcoming tumor resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapy
Background:
- Photodynamic therapy (PDT) is effective for superficial lesions but struggles with hypoxic tumors, such as head and neck squamous cell carcinoma (HNSCC).
- Tumor resistance mechanisms, particularly spatial heterogeneity in hypoxic regions, limit PDT's clinical success.
- Current strategies to reverse hypoxia often involve complex nanomaterials with long development times.
Purpose of the Study:
- To identify actionable molecular targets within tumor spatial heterogeneity to overcome PDT resistance in HNSCC.
- To investigate the role of Interleukin-1 alpha (IL1A) in mediating resistance to PDT in hypoxic tumors.
- To evaluate the therapeutic potential of blocking the IL-1α signaling pathway to enhance PDT efficacy.
Main Methods:
- Spatial transcriptomic profiling of HNSCC specimens to identify molecular gradients and key upregulated transcripts in hypoxic areas.
- In vitro and in vivo functional analyses to determine the role of IL-1α in PDT resistance, including its effect on the NF-κB pathway.
- Treatment of cellular models and patient-derived organoids (PDOs) with a selective IL-1 receptor 1 (IL-1R1) antagonist (AF12198) to assess its impact on PDT efficacy.
Main Results:
- Spatial transcriptomics revealed IL1A as the most significantly upregulated transcript in hypoxic HNSCC niches, correlating with poor clinical outcomes.
- PDT treatment induced a self-reinforcing resistance loop by further amplifying IL-1α expression.
- Hypoxic tumor-derived IL-1α was found to activate the NF-κB pathway, conferring resistance to PDT-induced oxidative stress.
- Selective blockade of IL-1R1 with AF12198 significantly enhanced PDT efficacy in both cell models and PDOs.
Conclusions:
- IL-1α acts as a critical mediator of intrinsic PDT resistance in hypoxic HNSCC by activating the IL-1α/IL-1R1/NF-κB axis.
- Targeting this axis represents a clinically actionable strategy to improve PDT outcomes.
- Repurposing existing clinical IL-1 inhibitors offers a promising approach to enhance PDT efficacy, supported by robust preclinical data leveraging spatial heterogeneity insights.
