Adult human skin contains nearly twice as many T cells as the peripheral blood, which include tissue-resident memory T cells. However, the precise mechanisms maintaining tissue-resident memory T cells in the healthy skin remain unclear. Using normal human skin samples, we find that Langerhans cells (LCs) contact T cells in the epidermis of the elderly. LCs with high HLA-II, CD86, and PD-L2 expression directly contacted PD-1⁺ tissue-resident memory T cells and CTLA-4⁺ regulatory T cells in the epidermis, indicating an axis of peripheral tolerance in a steady state. Environmental insults, UVB radiation, and hapten downregulated HLA-II and CD86 on LCs in the epidermis, suggesting that disruption of LC–T cell tolerogenic axis contributes to skin inflammation. Interestingly, immune checkpoint blockade therapy was associated with decreased epidermal LC–T cell contact in the normal skin of patients with cancer affected by cutaneous immune-related adverse events. Collectively, our findings indicate that LCs may contribute to T cell tolerance in the epidermis.

The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus–5-fluorouracil (calcipotriol-plus–5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus–5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4 ⁺ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus–5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.

Background: A notable trend has been observed toward procedural interventions for periorbital hyperpigmentation (POH), with a variety of pharmacological and nonpharmacological treatment modalities being introduced. This systematic review aims to provide a comprehensive evaluation of these diverse procedural treatments for POH in the medical literature. Method: A systematic search was performed in major databases up to 2023, and studies were evaluated for clinical improvement, patient satisfaction, and adverse events. The retrieved studies were categorized as lasers and light therapies, chemical peels, PRP, carboxytherapy, fillers and injections, microneedling, and combination therapies. Results: A total of 33 studies involving 1320 patients were evaluated. The meta‐analysis of improvement rates revealed that lasers (fractional CO ₂ and Q‐switched or long‐pulsed Nd: YAG) and combination treatments (microneedling + chemical peels or fillers + lasers) demonstrated the highest efficacy, with 82% and 75% of patients experiencing excellent or good (> 50%) improvement, respectively. Chemical peels, carboxytherapy, and PRP were less effective, benefiting 63%, 54%, and 44% of patients in the same category, respectively. Although fillers and autologous fat injections showed marked improvement in 94% and 74% of patients, the comparison of their results was limited due to their representation by a single study in each category. Considering the meta‐analysis of satisfaction rates, lasers and combination treatments also led, with 82% and 75% of patients expressing over 50% satisfaction with treatment, respectively. Adverse events were generally mild and transient across treatments. Common side effects of lasers included transient burning and erythema. The fractional CO ₂ laser was associated with discomfort, pain, and edema, with a shorter duration of swelling and erythema when combined with PRP. Q‐switched and picosecond Nd:YAG lasers had higher postinflammatory hyperpigmentation rates compared to carboxytherapy and the picosecond 755‐nm laser. The most common adverse effect of chemical peeling was erythema, with glycolic acid showing the maximum incidence. Conclusion: This systematic review reveals that lasers and combination therapies are the most effective and satisfactory treatments for POH, with generally mild and transient adverse events. However, further studies comprising larger sample sizes, multiple‐arm designs, and longer follow‐ups are needed to enable more robust comparisons.

Background/Objectives: Chronic inflammation is a key driver of cancer. Interleukin 33 (IL-33) has emerged as a crucial factor involved in the pathogenesis of cancer-prone chronic inflammation. IL-33 functions as a cytokine and a nuclear protein to initiate chronic inflammation and cancer. However, small molecules capable of suppressing IL-33 expression to block its cytokine and nuclear functions are underexplored. Methods: The impact of tropisetron on IL-33 expression and its role in suppressing pancreatitis and pancreatitis-mediated pancreatic cancer were examined. Results: We demonstrate that tropisetron suppresses IL-33 expression, with high potential to serve as a novel therapeutic strategy for preventing chronic inflammation and its cancer sequela. Through screening 1018 Food and Drug Administration (FDA)-approved drugs, we discovered that tropisetron, a 5-hydroxytryptamine type 3 (5-HT3) antagonist commonly used to prevent and treat nausea and vomiting, effectively blocked IL-33 expression by suppressing IRF3 activation. Tropisetron inhibited pancreatitis and its progression to pancreatic cancer in mice. Conclusions: Tropisetron is an IL-33 inhibitor and can provide a novel therapeutic strategy to prevent and treat chronic pancreatitis and its associated cancer.