This study establishes iCAFs and γδT cell loss as central drivers of cSCC aggressiveness and nominates CXCL8/TGFβ/IGFBP7 dysregulation as a biomarker framework for risk stratification. Collectively, these findings unveil actionable therapeutic targets and provide a molecular basis for personalizing management strategies, particularly for identifying and treating very highrisk cSCC patients who may benefit from intensified surgical approaches, adjuvant therapies, or novel targeted interventions.

3 days ago

Journal

CXCL8 (Chemokine (C-X-C motif) ligand 8) • TGFB1 (Transforming Growth Factor Beta 1) • IGFBP7 (Insulin Like Growth Factor Binding Protein 7)

COMBINE-EGFR-1: A Trial to Find Out How Safe REGN7075 is and How Well it Works in Combination With Cemiplimab for Adult Participants With Advanced Cancers (clinicaltrials.gov)

P1/2, N=933, Recruiting, Regeneron Pharmaceuticals | Trial completion date: Dec 2026 --> Apr 2027

4 days ago

Trial completion date

Avastin (bevacizumab) • Libtayo (cemiplimab-rwlc) • Lonsurf (trifluridine/tipiracil)

Study of Afatinib in Advanced Cutaneous Squamous Cell Carcinoma (clinicaltrials.gov)

P2, N=25, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Mar 2026 --> Sep 2026

4 days ago

Trial primary completion date

Gilotrif (afatinib)

Loss of the translational repressor 4E-BP1 promotes skin carcinogenesis. (PubMed, Front Pharmacol)

Analysis of human SCC specimens revealed elevated 4E-BP1 phosphorylation together with increased proliferative and angiogenic markers and activation of the mTOR signaling pathway, mirroring molecular features observed in 4E-BP1-deficient tumors. Collectively, these findings establish 4E-BP1 as a tumor suppressor in skin carcinogenesis that constrains both proliferative and angiogenic processes, underscoring the contribution of dysregulated translation to SCC development.

4 days ago

Journal

EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)

Pembrolizumab in Treating Patients With Rare Tumors That Cannot Be Removed by Surgery or Are Metastatic (clinicaltrials.gov)

P2, N=157, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2028 | Trial primary completion date: Dec 2025 --> Dec 2028

8 days ago

Trial completion date • Trial primary completion date • Tumor mutational burden

PD-L1 (Programmed death ligand 1)

Keytruda (pembrolizumab)

The SMAD-Pathway Mediates HMGB1-Induced Proliferation and Metastatic Progression in Cutaneous Squamous Cell Carcinoma Cells. (PubMed, Ann Dermatol)

These data imply that HMGB1 acts as a tumor-promoting factor in cSCC.

8 days ago

Journal

CDK4 (Cyclin-dependent kinase 4) • CDK6 (Cyclin-dependent kinase 6) • SOX2 • HMGB1 (High Mobility Group Box 1) • TP63 (Tumor protein 63)

Pembrolizumab Combined With Cetuximab for Treatment of Recurrent/Metastatic Head & Neck Squamous Cell Carcinoma (clinicaltrials.gov)

P2, N=78, Completed, University of California, San Diego | Active, not recruiting --> Completed | Trial completion date: May 2026 --> Sep 2025 | Trial primary completion date: Nov 2025 --> Jul 2025

9 days ago

Trial completion • Trial completion date • Trial primary completion date

Keytruda (pembrolizumab) • Erbitux (cetuximab)

10d

NCI-2018-01313: Cemiplimab in Treating Patients With Recurrent and Resectable Stage II-IV Head and Neck Cutaneous Squamous Cell Cancer Before Surgery (clinicaltrials.gov)

P2, N=44, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

10 days ago

Trial completion date • Trial primary completion date

Libtayo (cemiplimab-rwlc)

13d

Methylenetetrahydrofolate dehydrogenase 2 promotes cutaneous squamous cell carcinoma progression by reprogramming metabolism and interacting with fatty acid synthase. (PubMed, Int J Biol Macromol)

Mechanistically, MTHFD2 promotes cSCC progression by sustaining glycolytic metabolism and redox homeostasis, while also exerting a non-metabolic function through interaction with fatty acid synthase (FASN) to activate the PI3K-AKT signaling pathway. Importantly, pharmacological inhibition of MTHFD2 effectively suppressed cSCC cell proliferation in vitro and tumor growth in vivo, highlighting MTHFD2 as a promising therapeutic target.

13 days ago

Journal

FASN (Fatty acid synthase) • MTHFD2 (Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2)

14d

Talimogene Laherparepvec and Panitumumab for the Treatment of Locally Advanced or Metastatic Squamous Cell Carcinoma of the Skin (clinicaltrials.gov)

P1, N=5, Terminated, Rutgers, The State University of New Jersey | Active, not recruiting --> Terminated; slow accrual

14 days ago

Trial termination • Tumor mutational burden

Vectibix (panitumumab) • Imlygic (talimogene laherparepvec)