PI3Kγ Deficiency Suppresses Cutaneous Squamous Cell Carcinoma Formation by Modulating the Tumour Microenvironment Rather Than by Directly Regulating Keratinocyte Proliferation

ABSTRACT Phosphatidylinositol‐3 kinase (PI3K) is a central regulator of cell proliferation, survival, metabolism, and migration via the downstream AKT/mTOR pathway. Although activating mutations in the catalytic subunit of PI3Kα (p110α) have been documented in various cancers, including cutaneous squamous cell carcinoma (cSCC), the role of PI3Kγ (p110γ), which is predominantly expressed in immune cells, remains poorly defined in cSCC. To elucidate the function of p110γ in cSCC development, we compared tumour formation in wild‐type and p110γ‐ deficient mice using both a chemical carcinogenesis model and a syngeneic cSCC cell implantation model. While genetic deletion or pharmacological inhibition of PI3Kγ did not affect keratinocyte proliferation or migration in vitro, p110γ‐ deficient mice exhibited significantly delayed tumour onset, reduced tumour burden, and suppressed growth of implanted cSCC tumours in vivo. Immunohistochemical analyses revealed that total CD4 + T cell infiltration was unchanged, whereas CD8 + cytotoxic T cell infiltration was markedly increased and FoxP3 + regulatory T cells were significantly reduced in tumours from p110γ‐deficient mice, resulting in a substantially elevated CD8 + /FoxP3 + ratio. Immunoblot analyses of tumour lysates further demonstrated increased CD8 expression and enhanced NF‐κB p65 phosphorylation in p110γ‐deficient tumours. These results indicate that PI3Kγ contributes to cSCC development not by directly driving tumour cell proliferation but by shaping an immunosuppressive tumour microenvironment. Targeting PI3Kγ may therefore represent a promising immunotherapeutic strategy to enhance cytotoxic T‐cell–mediated antitumour immunity in cSCC.