# Advances in Targeted and Immunotherapy for High-Risk Cutaneous Malignancies

**Authors:** Amy J. Petty, Drew A. Emge, Adela R. Cardones

PMC · DOI: 10.32604/or.2025.073383 · Oncology Research · 2026-02-24

## TL;DR

This paper reviews recent advances in immunotherapy for treating high-risk skin cancers like basal cell carcinoma, squamous cell carcinoma, and melanoma.

## Contribution

The paper synthesizes current evidence and ongoing clinical trials of immunotherapy in three major skin cancer types.

## Key findings

- Immunotherapy has transformed treatment options for advanced skin cancers.
- Molecular mechanisms and biomarkers of immune responsiveness are being explored.
- Integration of immunotherapy into dermatology is shifting toward precision medicine.

## Abstract

Skin cancer remains the most commonly diagnosed malignancy worldwide, with basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma representing the most clinically significant types. While traditional treatments are effective for early-stage disease, advanced or metastatic cases often pose significant therapeutic challenges. Patients with high-risk or recurrent disease face limited options and poor prognoses. The emergence of immunotherapy has dramatically transformed the treatment landscape across multiple cancer types, including cutaneous malignancies. This review highlights recent advancements in immunotherapeutic strategies for BCC, cSCC, and melanoma, underscoring their growing importance in dermatologic oncology. We synthesize current evidence and ongoing clinical trials for immunotherapy across these three skin cancer types. We also explore the molecular mechanisms underpinning immune responsiveness and potential biomarkers of response. As immunotherapy continues to expand within dermatology, understanding its role, limitations, and future directions is essential for optimizing patient care. The integration of immunotherapy into dermatologic practice represents not only a therapeutic innovation but also a shift toward precision medicine in cutaneous oncology.

## Linked entities

- **Diseases:** basal cell carcinoma (MONDO:0005341), cutaneous squamous cell carcinoma (MONDO:0002529), melanoma (MONDO:0005105)

## Full-text entities

- **Genes:** IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, GNA11 (G protein subunit alpha 11) [NCBI Gene 2767] {aka FBH, FBH2, FHH2, GNA-11, HG1K, HHC2}, TERT (telomerase reverse transcriptase) [NCBI Gene 7015] {aka CMM9, DKCA2, DKCB4, EST2, PFBMFT1, TCS1}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, IL23A (interleukin 23 subunit alpha) [NCBI Gene 51561] {aka IL-23, IL-23A, IL23P19, P19, SGRF}, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) [NCBI Gene 6098] {aka MCF3, ROS, c-ros-1}, GNAQ (G protein subunit alpha q) [NCBI Gene 2776] {aka CMAL, G-ALPHA-q, GAQ, SWS}, SF3B1 (splicing factor 3b subunit 1) [NCBI Gene 23451] {aka Hsh155, MDS, PRP10, PRPF10, SAP155, SF3b155}, NF1 (neurofibromin 1) [NCBI Gene 4763] {aka NFNS, VRNF, WSS}, VEGFC (vascular endothelial growth factor C) [NCBI Gene 7424] {aka Flt4-L, LMPH1D, LMPHM4, VRP}, EIF1AX (eukaryotic translation initiation factor 1A X-linked) [NCBI Gene 1964] {aka EIF1A, EIF1AP1, EIF4C, eIF-1A, eIF-4C}, DAPK1 (death associated protein kinase 1) [NCBI Gene 1612] {aka DAPK, ROCO3}, CTLA4 (cytotoxic T-lymphocyte associated protein 4) [NCBI Gene 1493] {aka ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4}, ALK (ALK receptor tyrosine kinase) [NCBI Gene 238] {aka ALK1, CD246, NBLST3}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, LAG3 (lymphocyte activating 3) [NCBI Gene 3902] {aka CD223}, KIT (KIT proto-oncogene, receptor tyrosine kinase) [NCBI Gene 3815] {aka C-Kit, CD117, MASTC, PBT, SCFR}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, JAK1 (Janus kinase 1) [NCBI Gene 3716] {aka AIIDE, JAK1A, JAK1B, JTK3}, PYCARD (PYD and CARD domain containing) [NCBI Gene 29108] {aka ASC, CARD5, TMS, TMS-1, TMS1}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, NOTCH2 (notch receptor 2) [NCBI Gene 4853] {aka AGS2, HJCYS, hN2}, PDCD1 (programmed cell death 1) [NCBI Gene 100533201], PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, HLA-G (major histocompatibility complex, class I, G) [NCBI Gene 3135] {aka MHC-G}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, RELA (RELA proto-oncogene, NF-kB subunit) [NCBI Gene 5970] {aka AIF3BL3, CMCU, NFKB3, p65}, IL13 (interleukin 13) [NCBI Gene 3596] {aka IL-13, P600}, IL5 (interleukin 5) [NCBI Gene 3567] {aka EDF, IL-5, TRF}, GLI2 (GLI family zinc finger 2) [NCBI Gene 2736] {aka CJS, HPE9, PHS2, THP1, THP2}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, CCL17 (C-C motif chemokine ligand 17) [NCBI Gene 6361] {aka A-152E5.3, ABCD-2, SCYA17, TARC}, CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, JAK2 (Janus kinase 2) [NCBI Gene 3717] {aka JTK10}, Yap1 (yes-associated protein 1) [NCBI Gene 22601] {aka Yap, Yap65, Yki, Yorkie}, RASSF1 (Ras association domain family member 1) [NCBI Gene 11186] {aka 123F2, NORE2A, RASSF1A, RDA32, REH3P21}, BMP1 (bone morphogenetic protein 1) [NCBI Gene 649] {aka OI13, PCOLC, PCP, TLD}, GREM1 (gremlin 1, DAN family BMP antagonist) [NCBI Gene 26585] {aka C15DUPq, CKTSF1B1, CRAC1, CRCS4, DAND2, DRM}, IL2 (interleukin 2) [NCBI Gene 3558] {aka IL-2, TCGF, lymphokine}, Mdk (midkine) [NCBI Gene 17242] {aka MK, Mek}, BAP1 (BRCA1 associated deubiquitinase 1) [NCBI Gene 8314] {aka HUCEP-13, KURIS, TPDS1, UBM2, UCHL2, UVM2}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, SUFU (SUFU negative regulator of hedgehog signaling) [NCBI Gene 51684] {aka BCNS2, JBTS32, PRO1280, SUFUH, SUFUXL}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, CDK4 (cyclin dependent kinase 4) [NCBI Gene 1019] {aka CMM3, MCPH31, PSK-J3}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 397157] {aka VEGF}, FRZB (frizzled related protein) [NCBI Gene 2487] {aka FRE, FRITZ, FRP-3, FRZB-1, FRZB-PEN, FRZB1}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, IFNA1 (interferon alpha 1) [NCBI Gene 3439] {aka IFL, IFN, IFN-ALPHA, IFN-alphaD, IFNA13, IFNA@}, G0S2 (G0/G1 switch 2) [NCBI Gene 50486], CXCL12 (C-X-C motif chemokine ligand 12) [NCBI Gene 6387] {aka IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1}, MMP11 (matrix metallopeptidase 11) [NCBI Gene 4320] {aka SL-3, ST3, STMY3}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, CDH1 (cadherin 1) [NCBI Gene 999] {aka Arc-1, BCDS1, CD324, CDHE, ECAD, LCAM}, PTCH1 (patched 1) [NCBI Gene 5727] {aka BCNS, BCNS1, NBCCS, PTC, PTC1, PTCH}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, IL22 (interleukin 22) [NCBI Gene 50616] {aka IL-21, IL-22, IL-D110, IL-TIF, ILTIF, TIFIL-23}, GLI1 (GLI family zinc finger 1) [NCBI Gene 2735] {aka GLI, PAPA8, PPD1}
- **Diseases:** metastases (MESH:D009362), lentigo maligna melanoma (MESH:D018327), muscle cramps (MESH:D009120), viral infections (MESH:D014777), carcinogenic (MESH:D011230), hypertension (MESH:D006973), colitis (MESH:D003092), stage III disease (MESH:D007676), congenital nevi (MESH:D009506), toxicities (MESH:D064420), weight loss (MESH:D015431), Bowen's disease (MESH:D001913), nodal (MESH:D013611), TEAEs (MESH:D000093742), epidermodysplasia verruciformis (MESH:D004819), Cutaneous Malignancies (MESH:C562393), uveal melanomas (MESH:C536494), BCC (MESH:D002280), stage IIB/C (MESH:D062706), CSD (MESH:D013474), Melanoma (MESH:D008545), chronic inflammation (MESH:D007249), II disease (MESH:D004194), dysgeusia (MESH:D004408), Cancer (MESH:D009369), HHIs (MESH:D054179), Basal Cell Nevus Syndrome (MESH:D001478), basosquamous carcinoma (MESH:D002281), SCC of the head and neck (MESH:D006258), Aks (MESH:D055623), NMSCs (MESH:D012878), alopecia (MESH:D000505), interstitial pneumopathy (MESH:C535590), carcinogenesis (MESH:D063646), stage IIIB-IV (MESH:C566890), fatigue (MESH:D005221), Merkel cell carcinoma of the skin (MESH:D015266), blue nevi (MESH:D018329), stage IIIB, IIIC, or IV (MESH:C566891), Cutaneous Squamous Cell Carcinoma (MESH:D002294)
- **Chemicals:** EORTC 18071 (-), tacrolimus (MESH:D016559), Cemiplimab (MESH:C000627974), Pembrolizumab (MESH:C582435), Sonidegib (MESH:C561435), Cetuximab (MESH:D000068818), prednisone (MESH:D011241), steroid (MESH:D013256), dabrafenib (MESH:C561627), arsenic (MESH:D001151), imiquimod (MESH:D000077271), Nivolumab (MESH:D000077594), creatinine (MESH:D003404), Vismodegib (MESH:C538724), binimetinib (MESH:C581313), relatlimab (MESH:C000721227), vemurafenib (MESH:D000077484), atezolizumab (MESH:C000594389), trametinib (MESH:C560077), encorafenib (MESH:C000601108), CPDs (MESH:D011740), Ipilimumab (MESH:D000074324), pyrimidine (MESH:C030986)
- **Species:** Homo sapiens (human, species) [taxon 9606], Human papillomavirus 16 (serotype) [taxon 333760], Halogranum sp. PV5 (species) [taxon 1089731], Mus musculus (house mouse, species) [taxon 10090], Human papillomavirus (species) [taxon 10566]
- **Mutations:** BRAFV600K, D473H, cytosine-to-thymine, C > T, T > A, BRAFV600E, W535L
- **Cell lines:** CSCC-1 — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_DF76)

## Full text

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## Figures

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## References

215 references — full list in the complete paper: https://tomesphere.com/paper/PMC12963654/full.md

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Source: https://tomesphere.com/paper/PMC12963654