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Review
. 2025 Apr 9;23(1):129.
doi: 10.1186/s12957-025-03791-5.

Skin microbiome influences the progression of cutaneous squamous cell carcinoma through the immune system

Zijian Zhang #  1 , Lili Liang #  2   3 , Xiaoke Jiang  4 , Jixuan Shan  1 , Siying Li  4 , Jie Liu  4 , Qinyi Dong  1 , Xinman Wang  4 , Han Zhang  4
Affiliations
Review

Skin microbiome influences the progression of cutaneous squamous cell carcinoma through the immune system

Zijian Zhang et al. World J Surg Oncol. .

Abstract

Cutaneous squamous cell carcinoma (cSCC) is a type of skin tumor that develops in the epithelial cells. This disease has the second highest incidence of human skin cancers, with a high metastatic rate. While ultraviolet radiation significantly contributes to the genomic changes that support cSCC development, the dysbiosis of the skin microbiome and influence of the immune system also play important roles in this process. In this review, we discuss the effects of skin microbes and their metabolites on the immune system, including innate immune cells, T cells, and cytokines. We also discuss how Staphylococcus aureus and human papillomavirus can affect cSCC by impacting the immune system. Furthermore, we explore the antagonism of symbiotic microorganisms with cSCC-associated pathogens and their potential as novel therapeutic modalities.

Keywords: Cutaneous squamous cell carcinoma; Immune system; Microbiome; Skin; Skin cancer.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: N/A. Third party material: No, all of the material is owned by the authors and/or no permissions are required. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Multiple skin microbiotas have been associated with skin cancers (including non-melanoma, malignant melanoma, and Merkel cell carcinoma). Compared with healthy skin, there were differences in the presence of Human papillomavirus, Staphylococcus aureus, Staphylococcus epidermis, Malazzia, Cutibacterium, Propionibacterium acnes, and Merkel cell polyomavirus in non-melanoma skin. Merkel cell polyomavirus is also the main cause of Merkel cell carcinoma. Human papillomavirus, Fusobacterium, Trueperella, Human endogenous retroviruses, Propionibacterium acnes, and Corynebacterium in malignant melanoma were significantly different from those in normal skin
Fig. 2
Fig. 2
Major known HPV genera. HPV infection is an important factor in the pathogenesis of many squamous cell carcinomas, and more than 150 HPV genotypes have been fully sequenced, and HPV types are classified into five genera based on the nucleotide sequence of the L1 gene: α, β, γ, ν, and μ
Fig. 3
Fig. 3
Staphylococcus aureus affects and drives the progression of cSCC of the skin. Staphylococcus aureus affects and drives the progression of cSCC of the skin in a variety of ways. Staphylococcus aureus secretion group can enhance the expression of IL- 6, IL- 8 and TNF-α genes in human keratinocytes, and promote the formation of tumor microenvironment in the skin. Staphylococcus aureus strains can secrete compounds similar to ultraviolet irradiation, which can promote the development of cSCC by expressing biomarkers of cSCC, while affecting the expression of MMP and kallikrein serine protease, reducing skin barrier function, damaging DNA repair and skin barrier function, and thus promoting epidermal hyperplasia and cSCC development
Fig. 4
Fig. 4
Regulation of skin microecology by skin symbiotic bacteria. Skin symbiosis has been studied, they have an impact on the immune microecology, and play a corresponding role in skin cancer is undoubtedly, they can produce free fatty acids, reduce the surface pH, form an acidic environment, inhibit the colonization of pathogenic bacteria. Some skin symbiotic bacteria have antagonistic properties with cSCC-associated pathogens, and they can secrete AMPs or antibacterial compounds to fight skin pathogens. In addition, it can activate γδT cells and up-regulate the expression of perforin- 2 in human skin, enhancing the ability to inhibit pathogens
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