Cutaneous squamous cell carcinoma (cSCC) is a malignant skin cancer which is derived from epidermal keratinocytes, and long-term exposure to ultraviolet rays is its main risk factor. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) is a crucial gene for the formation and stability of collagen intermolecular cross-links, being vital in the development of cancer. Nevertheless, the interaction between cSCC and PLOD2 has not been elucidated. Here, we found PLOD2 upregulated in human cSCC. Its knockdown in cSCC cells suppressed proliferation, migration, invasion, and angiogenesis while inducing apoptosis and cell cycle arrest; overexpression promoted these malignant phenotypes. In mouse xenografts, PLOD2 knockdown inhibited tumor growth and collagen deposition. Furthermore, in a DMBA/TPA-induced carcinogenesis model, topical PLOD2 inhibition by minoxidil suppressed tumor development as well. Mechanistically, our studies revealed that PLOD2 acts as a key downstream effector of STAT3 to activate ERK and AKT signaling evidenced by rescue experiments. As a result, our study not only establishes the STAT3/PLOD2/ERK-AKT axis as a key driver of cSCC but also identifies the clinically approved drug minoxidil as a potent PLOD2 inhibitor, demonstrating immediate promise as a repurposed therapeutic agent.

Cemiplimab versus historical systemic treatments for locally advanced or metastatic cutaneous squamous cell carcinomas: Results from the French study TOSCA.

Incidence and Impact of ctDNA Positivity in Cutaneous Squamous Cell Carcinoma

Kidney transplant recipients (KTRs) are at increased risk of developing cutaneous squamous cell carcinoma (cSCC), particularly when treated with calcineurin inhibitors (CNI), which are strongly associated with tumorigenesis. In contrast, mTOR inhibitors such as sirolimus have demonstrated antitumor activity, but their role in secondary prevention of cSCC remains unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the impact of switching from a CNI-based to an mTOR inhibitor-based immunosuppressive regimen on the incidence of cSCC in KTRs with prior cSCC. MEDLINE, EMBASE, CENTRAL, and trial registries were searched through June 2025. Incidence rate ratios (IRRs) for cSCC and risk ratios (RRs) for adverse events (AEs) were pooled using a random-effects model. Risk of bias was assessed with Cochrane RoB2. The study was registered in PROSPERO prior to data extraction (CRD42024583966). The study was unfunded. Four RCTs (393 patients) were included. Sirolimus significantly reduced 2-year cSCC incidence (IRR 0.51, 95% CI 0.39-0.67). However, discontinuation was more frequent (RR 8.60, 95% CI 1.95-37.93) due to AEs. No significant differences in mortality or graft rejection were found. Certainty of evidence was high for cSCC incidence and low for adverse events due to heterogeneity and selective reporting. In conclusion, sirolimus reduces secondary cSCC risk but increases AEs; patient selection and monitoring are essential. Trial Registration: PROSPERO number: CRD42024583966.

Node-Positive Cutaneous Squamous Cell Carcinoma in the Era of Immunotherapy: A Single Institution Experience

Multidrug-resistance proteins and glucose transporter expression in cutaneous squamous cell carcinoma and adjacent healthy tissue in hairless mice

Navigating the Diagnostic Maze of Cutaneous Squamous Cell Carcinoma Nodal Assessment

Actinic field cancerization is considered a chronic and relapsing condition. Thus, long-term clearance and prevention of cutaneous squamous cell carcinoma should be the fundamental goal of treatment. This trial aims to compare long-term outcomes of two novel field treatments for actinic keratoses. The investigator-initiated intraindividual randomised controlled and evaluator-blinded trial compared fractional laser-assisted artificial- or natural daylight photodynamic therapy to daylight photodynamic therapy alone, as a split-head comparison of 60 patients with ≥ two actinic keratoses of the head, on a two-year follow-up. The intention-to-treat analysis showed a significantly higher lesion-specific two-year sustained clearance with the laser-assisted treatment (p=0.003, 56.3% (147/261)) vs. 43.0% (108/251) for daylight photodynamic therapy alone. Additionally, 45.6% (26/57) of patients achieved two-year sustained partial clearance in the laser-assisted treatment compared to 31.6% (18/57) in daylight photodynamic therapy alone (p=0.064). Correspondingly, 15.8% (9/57) compared to 7.0% (4/57) of patients achieved sustained complete clearance (p=0.070). No squamous cell carcinomas developed on the treatment field, and in total three Bowen's diseases. Laser-assisted daylight photodynamic therapy seems to achieve a higher long-term sustained clearance and may be superior also on long-term compared to daylight photodynamic therapy alone in the treatment of actinic keratosis of all grades.

Ultraviolet A plays a protective role in ultraviolet B-induced squamous cell carcinoma through c-Fos/XRCC4 axis.

CDKN2A, ITGA3, SMAD4 and SIRT7 gene expression in human cutaneous squamous cell carcinoma development and pre-clinical diagnosis.

Skin cancer and vitamins: In theory and practice.

Directions in Nonmelanocytic Tumors: Squamous Cell Carcinoma and Merkel Cell Carcinoma.

Current landscape of PDT-based combination therapy for cutaneous squamous cell carcinoma: From molecular mechanisms to clinical practice.

High-dose-rate interstitial brachytherapy may provide durable local control with acceptable cosmetic outcomes in carefully selected patients with xeroderma pigmentosum and cutaneous squamous cell carcinoma. This long-term follow-up case questions the absolute contraindication of radiotherapy in XP and underscores the importance of individualized treatment planning based on underlying DNA repair mechanisms.

Integrated multidisciplinary care reduces time to treatment in patients with advanced cutaneous squamous cell carcinoma: A retrospective cohort study.

Clinical Equipoise and Unimproved Outcomes following Post-Transplant Cutaneous Squamous Cell Carcinoma

Actinic keratosis (AK) is a prevalent, chronic skin condition and a precursor to cutaneous squamous cell carcinoma. Effective, patient-friendly therapies that target both visible and subclinical lesions are essential. Tirbanibulin, a topical microtubule inhibitor, is the latest treatment approved in the USA and European Union (EU) for treating non-hyperkeratotic, non-hypertrophic AK on the face and scalp. This study aimed to assess the overall value of tirbanibulin for treating AK on the face or scalp across Germany, Italy, and Spain and to identify key value drivers using a multi-stakeholder perspective. This study used a multi-criteria decision analysis (MCDA) to assess the holistic value of tirbanibulin compared with 5-fluorouracil 4% (5FU-4%) across Germany, Italy, and Spain. The validated EVIDEM MCDA framework (tenth edition) included eleven criteria related to disease burden, treatment benefits, evidence quality, and comparative outcomes. A total of 18 participants-dermatologists, payers, and patients-evaluated the treatments in a two-phase process. Phase 1 involved weighing the criteria, and phase 2 involved scoring clinical, economic, and patient-reported evidence for both treatments. Results from both phases were used to calculate an estimated value. The approach supports transparent, stakeholder-informed decision-making for AK treatment. All criteria were rated as relevant, with the greatest importance assigned to "comparative safety/tolerability," "quality of evidence," and "comparative efficacy." Tirbanibulin received positive scores across all criteria, particularly for "expert consensus/guidelines," "quality of evidence," and "size of the affected population." The final estimated value of tirbanibulin was 0.622 on a -1 to +1 scale, indicating high perceived value. Value estimations were consistent across stakeholder types, with slight country-level variations. Overall, participants recognized tirbanibulin as a valuable treatment for AK, on the basis of robust evidence, favorable safety/tolerability and patient-reported outcomes (PRO) profiles, and alignment with clinical guidelines, with similar efficacy compared with 5FU-4%.

HSR26-247: Real-World Quality of Life in Patients Treated With Cemiplimab for Advanced Cutaneous Squamous Cell Carcinoma: Results of CemiplimAb Survivorship Epidemiology (CASE) Study.

Rhenium-188 resin therapy for non-melanoma skin cancer.

Abstract The global incidence of cutaneous squamous cell carcinoma (CSCC) has increased significantly over the past 30 years. In the UK, between 2000 and 2010, there was a 34% rise in cases among males and a 39% rise among females. Non-melanoma skin cancers (NMSC) account for approximately 20% of all newly diagnosed malignancies and 90% of skin cancers worldwide (1). Advanced CSCC includes both locally advanced (laCSCC) and metastatic (mCSCC) disease, the latter involving regional or distant spread. Mortality rates in patients with advanced CSCC, particularly those with metastases, can exceed 70% in some cohorts (2). In recent years, immunotherapy has emerged as a promising treatment option, especially for patients with unresectable or treatment-resistant disease. Immune checkpoint inhibitors, particularly PD-1 inhibitors, have demonstrated significant clinical benefit, with trials reporting complete remission in over 60% of patients with advanced CSCC(3). Accordingly, the British Association of Dermatologists recommends their use in cases of locally advanced or metastatic disease. We present three cases of advanced CSCC with clinical and radiological regression following immunotherapy, illustrating its increasing role in treatment. Additionally, we review current literature on the efficacy and safety of immunotherapy, associated adverse effects, and the clinical challenges in managing advanced CSCC. As there remains no universally defined treatment pathway for patients with unresectable or metastatic disease, and with some patients becoming non-responsive to surgery or radiotherapy, systemic therapies such as immunotherapy represent a critical and evolving treatment strategy.