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JAK inhibition results in aggressive cutaneous squamous cell carcinoma through MAPK pathway activation and shapes the tumor immune microenvironment to create novel therapeutic opportunities [RNA-seq]

ABSTRACT: Secondary malignancies are the most feared adverse effects of cancer therapies. In this study, we explore the oncogenic effects of the JAK inhibitor ruxolitinib on the skin. First, we demonstrate an epidemiological association between ruxolitinib exposure and development of aggressive cutaneous squamous cell carcinoma (cSCC), by conducting a disproportionality analysis on international pharmacovigilance data and a large local cohort study. We next demonstrate the causal link between ruxolitinib treatment and cSCC development, using in vitro and in vivo models. Mechanistically, we reveal that ruxolitinib induces transformation of pre-malignant keratinocytes into aggressive cSCC by activating the MAPK pathway through the COT kinase. Intriguingly, ruxolitinib also reshapes the immune microenvironment of cSCC resulting in T regulatory cells reduction and T CD8+ cells increase. Ruxolitinib-mediated immune microenvironment effects create new therapeutic opportunities by enhancing anti-PD1 treatment efficacy in cSCC and other immunotherapy resistant cancer types such as pancreatic cancer and acute myeloid leukemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE278530 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:Despite the demonstrated efficacy of immune checkpoint blockade therapies in various tumors, their efficacy in cervical cancer is limited by factors such as the need for positive PD-L1 expression and the development of drug resistance. A crucial pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), is highly expressed in various cancers and contributes to tumor progression by regulating inflammatory responses and the tumor microenvironment. The present study aimed to explore the role of macrophage migration inhibitory factors in cervical squamous cell carcinoma (CSCC) recurrence and metastasis. Western blotting, reverse transcription quantitative PCR, cell-counting kit 8 assay, flow cytometry, and ELISA were used to investigate the effects of MIF on CSCC progression and formation of inflammasomes. Transcriptome and proteome sequencing were combined to screen for key effector proteins of MIF. Moreover, in vitro co-culture experiments, Transwell assays, and flow cytometry were used to evaluate the roles of MIF and TSC22 domain family protein 3 (TSC22D3) as inflammatory tumor-promoting factors in macrophage recruitment and polarization induction. The results indicated that MIF was highly expressed in CSCC with lymph node metastasis, positively correlated with cervical cancer stage, and associated with poor prognosis. MIF was found to promote CSCC progression and linked to inflammasome activation. Multi-omics screening results indicated that TSC22D3 may be a crucial interacting gene of MIC. Moreover, MIF and TSC22D3 could facilitate inflammasome activation, macrophage recruitment, and M2 polarization. Therefore, MIF and TSC22D3 can induce macrophage infiltration in cervical cancer lesions and affect the tumor microenvironment by polarizing macrophages toward the M2 phenotype, promoting CSCC progression. This study highlights the potential of targeting the MIF-TSC22D3 axis as a novel therapeutic strategy and offering a promising avenue for improving the efficacy of immunotherapy in treatin

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JAK inhibition results in aggressive cutaneous squamous cell carcinoma through MAPK pathway activation and shapes the tumor immune microenvironment to create novel therapeutic opportunities [RNA-seq]

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