Type 2 immunity to the rescue: enhancing antitumor immunity for skin cancer prevention

Sep 23, 2026

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Cutaneous squamous cell carcinoma (cSCC) incidence and deaths continue to rise, making prevention of actinic keratosis (AK) precursors critical. The commentary highlights findings showing that type 2 immunity is necessary and sufficient for eliminating premalignant keratinocytes and preventing cSCC. Paired human biopsies indicate AK keratinocytes produce thymic stromal lymphopoietin (TSLP) and damage-associated signals that recruit Th2 cells. In mouse models, TSLP enables Th2 recruitment and IL-24–mediated keratinocyte death, suggesting a TSLP/Th2/IL-24 therapeutic target.

LanguageEnglish

CategoryHealthcare

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Pages4

Reading Time10 min

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Type 2 immunity to the rescue

cSCC prevention via elimination of actinic keratosis

Squamous cell carcinoma and field cancerization

Detection, treatment, and prevention of multiple primary lesions

Type 2 immunity in cancer immunosurveillance

The Journal of Clinical Investigation COMMENTARY Type 2 immunity to the rescue: enhancing antitumor immunity for skin cancer prevention Matthew D. Vesely,1 and Sean R. Christensen1,2 1Department of Dermatology, and 2Department of Surgery, Division of Plastic and Reconstructive Surgery, Yale School of Medicine, New Haven, Connecticut, USA. Cutaneous squamous cell carcinoma (cSCC) incidence and deaths continue to rise, underscoring the need for improved cSCC prevention. Elimination of actinic keratosis (AK) precursor lesions is a major strategy to prevent cSCC. Topical calcipotriol and 5-fluorouracil (5-FU) have been shown to eliminate AKs and reduce the risk of cSCC development, but the mechanism was undefined. In this issue of the JCI, Oka et al. demonstrate that type 2 immunity is necessary and sufficient for the elimination of premalignant keratinocytes and cSCC prevention. Paired biopsies from AK lesions and unaffected skin revealed that only keratinocytes from AKs produced thymic stromal lymphopoietin (TSLP) and damage-associated molecular patterns, resulting in selective recruitment of Th2 cells to the AK lesion. In mouse models of skin carcinogenesis, TSLP was necessary to recruit Th2 cells and trigger IL-24–mediated keratinocyte cell death. These findings suggest that the TSLP/Th2/IL-24 axis is a potential therapeutic target for SCC prevention. Squamous cell carcinoma and field cancerization Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in humans, accounting for over 1,000,000 cases and 5,000 deaths per year in the United States, and the incidence continues to rise (1– 3) . The primary risk factor for development of cSCC is exposure of the skin to mutagenic ultraviolet radiation (UVR) from the sun (1) . Unlike many internal malignancies, cSCC frequently presents with multiple primary tumors. Among patients with an initial diagnosis of cSCC, 42% will develop additional new primary cSCC within 5 years, and this risk increases to 72% in patients with two or more cSCCs (4) . A small fraction of patients, particularly those with immunosuppression, develop more than 10 primary cSCCs, and these patients exhibit markedly increased risk for metastasis and death (5) . Detection, treatment, and prevention of multiple primary lesions is a cornerstone of management of cSCC. The existence of multiple tumors within a region of skin subjected to UVR is termed field cancerization and is a unique feature of cancers of the skin (6) . While the development of systemic immune checkpoint inhibition has revolutionized the treatment of locally advanced or metastatic cSCC (7), these treatments do not necessarily solve the challenge of subsequent primary cSCC inpatients with field cancerization (8) . More effective and durable prevention strategies for cSCC are needed. In this issue of the JCI, Oka et al. describe the immunologic mechanism that may underlie a promising approach to cSCC prevention (9) . Patients with cSCC typically present with numerous precursor lesions of actinic keratosis (AK) prior to and simultaneously Related Article: [https://doi.org/10.1172/JCI183274](https://doi.org/10.1172/JCI183274) Conflict of interest: MDV has served as an advisor for SunPharma. SRC has served as an investigator for Sol-Gel Technologies and a consultant for Inhibitor Therapeutics and Castle Biosciences. Copyright: © 2025, Vesely et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Reference information: J Clin Invest. 2025;135(1):e188018 . [https://doi.org/10.1172/JCI188018](https://doi.org/10.1172/JCI188018) . with development of cSCC (10) . Although AKs are premalignant lesions that are not dermally invasive, they share many of the same UVR-induced driver mutations as cSCC, including loss-of-function mutations in TP53 and NOTCH1 (11) . Treatment of premalignant AKs represents an attractive strategy for cSCC prevention. Sev

FAQs

Why is preventing actinic keratosis (AK) important for skin cancer prevention?

Because AK lesions are major precursor targets for reducing the development of cutaneous squamous cell carcinoma (cSCC). Eliminating AKs helps lower subsequent cSCC risk.

What mechanism did the commentary attribute to type 2 immunity in cSCC prevention?

AK keratinocytes produce thymic stromal lymphopoietin (TSLP) and damage-associated molecular patterns, leading to selective recruitment of Th2 cells. In mouse models, TSLP supports Th2 recruitment and IL-24–mediated keratinocyte cell death.

How does the TSLP/Th2/IL-24 axis relate to potential therapy?

The findings suggest the TSLP/Th2/IL-24 signaling pathway could be a therapeutic target for preventing squamous cell carcinomas by promoting immune-mediated elimination of premalignant cells.

Sep 23, 2026

Uploaded by Jiven