By Pooja Toshniwal PahariaReviewed by Lauren HardakerMar 19 2026Researchers uncover how a psoriasis-like immune response can slow skin cancer development, revealing an unexpected protective role for inflammation in the earliest stages of tumor growth.
Study: Psoriasis-like disease prevents squamous skin tumor development by neutrophil-driven inflammation. Image credit: LightField Studios/Shutterstock.com
A new study published in Proceedings of the National Academy of Sciences challenges the belief that chronic inflammation always promotes cancer. The study shows that, under specific conditions, a psoriasis-type inflammatory response can limit tumor growth, highlighting the nuanced, context-dependent role of immunity in cancer development.
Using multiple mouse models, the study shows that neutrophil-driven inflammation is associated with and functionally contributes to limiting cutaneous squamous cell carcinoma (cSCC) by triggering tumor-suppressive mechanisms, including keratinocyte senescence and coordinated immune responses. Certain inflammatory environments in the skin may act as protective barriers against tumor development.
Amid rising rates of chronic inflammatory diseases and skin cancers, the findings suggest a need to refine how sustained immune activation is viewed in cancer risk, rather than broadly redefining it as protective.
Psoriasis-Like Inflammation Shows Unexpected Tumor-Suppressive Effects
Psoriasis is a persistent, immune-driven skin condition shaped by complex interactions between epidermal cells and recruited immune cells. Beyond the skin, it is associated with systemic inflammation and co-existing conditions such as psoriatic arthritis, metabolic disorders, and some malignancies. Epidemiological studies suggest an increased cSCC risk among individuals with extensive or chronic psoriasis, although this relationship remains complex and not fully resolved.
However, this link remains contradictory, as tumors frequently develop outside psoriatic lesions. This “skin cancer paradox” challenges the conventional view of inflammation as solely tumor-promoting and underscores the need to better understand its context-dependent effects.
Combining Tumor Grafts And Chemical Carcinogenesis To Test Cancer Risk
In the present study, researchers investigated the influence of chronic inflammation on the development of skin cancer. They used tumor cell grafts and chemical-induced skin cancer systems alongside inducible genetically modified mouse models of psoriasis-like disease.
The investigators induced psoriasis-like inflammation in R23K14 and CARDK14 mice using tamoxifen. They then injected PDVC57B cSCC cells intradermally and monitored tumor growth over eight weeks. The team evaluated disease severity using the psoriasis area and severity index (PASI) scores, alongside molecular and histological analyses of skin tissue.
The researchers examined tumor susceptibility in mice with established moderate-to-severe disease. To model tumor initiation under physiologically relevant conditions, they applied chemical carcinogen protocols involving 7,12-dimethylbenz[a]anthracene (DMBA) or 12-O-tetradecanoylphorbol-13-acetate (TPA). Subsequently, the team assessed epidermal changes, cell cycle regulation, and protein expression. They characterized immune cell infiltration at early stages, prior to tumor formation, using flow cytometry.
To uncover underlying mechanisms, the team performed single-cell ribonucleic acid (RNA) sequencing (scRNA-seq) of skin samples, focusing on immune–epithelial interactions. They analyzed neutrophil activation states and intercellular communication pathways, particularly between neutrophils and keratinocytes, using CellChat. Further subclustering identified distinct keratinocyte populations linked to proliferation and senescence. Lastly, they depleted neutrophils in vivo using anti-Ly6G antibodies to directly test their functional role in tumor suppression.
Neutrophil Expansion Drives Senescence And Limits Tumor Progression
The findings demonstrate that severe psoriasis-like inflammation suppresses cSCC development and chemically induced skin tumorigenesis. In transplantation models, tumor growth initially paralleled controls but declined from week five onward, with significant reductions associated with higher disease severity. In DMBA/TPA-induced carcinogenesis, approximately 40 % of mice with severe disease developed papillomas. However, over 50 % remained tumor-free, confirming a strong protective effect, with tumors arising predominantly in non-lesional skin rather than in inflamed areas.
This tumor suppression was associated with and partially mediated by a marked accumulation of neutrophils, which increased by up to 80-fold and comprised a substantial proportion of immune cells. These cells showed features consistent with an activated, tumor-suppressive N1-like phenotype, expressing cluster of differentiation 54 (CD54) and CD177, and releasing cytotoxic mediators, including myeloperoxidase, neutrophil elastase, and S100A8/A9. Evidence of neutrophil extracellular trap formation further indicated heightened activation, creating a highly inflammatory yet tumor-suppressive microenvironment.
At the epithelial level, keratinocytes showed increased proliferation, along with strong signatures of growth arrest and senescence, including elevated p16, p21, and p53 expression. The scRNA-seq analysis revealed reduced activity in key oncogenic pathways, such as epidermal growth factor (EGF) and wingless-related integration site (WNT) signaling, and a shift toward cell cycle arrest, with more cells in the G0/G1 phase. These changes were consistent with chronic inflammatory and oxidative stress.
Further analyses revealed extensive remodeling of immune–epithelial communication networks. Neutrophils acted as central regulators of inflammatory signaling and cellular stress. Notably, neutrophil depletion reduced inflammation, abolished keratinocyte senescence, and restored tumor growth, confirming a key functional role.
The findings show that neutrophil-driven inflammation is linked to increased keratinocyte senescence, forming a barrier that limits tumor initiation and progression, although some mechanistic aspects, such as direct tumor cell elimination, remain proposed rather than definitively proven. However, these findings are based on preclinical models, and further studies are needed to determine their relevance in human patients.
Translating Preclinical Immune Insights Into Safe Therapeutic Approaches
The findings suggest potential therapeutic avenues to harness neutrophil activation and inflammation-induced senescence to prevent cancer. Instead of broadly suppressing inflammation, amplifying tumor-suppressive immune responses, especially N1-like neutrophils, may represent a future strategy, although this remains speculative. Strategies that enhance neutrophil recruitment, activation, or effector functions could, in principle, help limit early tumor development but require careful validation.
Equally important is leveraging senescence as a protective mechanism. Inducing controlled, inflammation-driven senescence in epithelial cells may act as a barrier to malignant transformation, though this concept is still preclinical and could complement existing immunotherapies, particularly in resistant tumors. Translating these insights will require careful modulation of immune pathways to preserve antitumor benefits while avoiding harmful inflammation.
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Journal Reference
Tsokkou, P. et al. (2026). Psoriasis-like disease prevents squamous skin tumor development by neutrophil-driven inflammation. Proceedings of the National Academy of Sciences, 123(11), e2536378123. DOI: 10.1073/pnas.2536378123. https://www.pnas.org/doi/10.1073/pnas.2536378123
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