2. Academic Validation
  3. FAK-Dependent Reprogramming of IFN-γ Signaling through PYK2 Co-Inhibition Sensitizes Melanoma to Immune Checkpoint Blockade

FAK-Dependent Reprogramming of IFN-γ Signaling through PYK2 Co-Inhibition Sensitizes Melanoma to Immune Checkpoint Blockade

  • J Invest Dermatol. 2025 Oct 14:S0022-202X(25)03407-4. doi: 10.1016/j.jid.2025.09.376.
Yuto Mizuno 1,  Masanari Umemura 2,  Akane Nagasako 3,  Tomoko Akiyama 4,  Momoko Nagai 5,  Jo Nishino 5,  Jordan Ramilowski 6,  Yayoi Kimura 4,  Mamoru Kato 5,  Yukie Yamaguchi 7,  Yoshihiro Ishikawa 8
Affiliations

Affiliations

  • 1 Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
  • 2 Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan. Electronic address: umemurma@yokohama-cu.ac.jp.
  • 3 Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
  • 4 Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa, Japan.
  • 5 Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, 104-0045, Japan.
  • 6 Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
  • 7 Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa, Japan.
  • 8 Yokohama City University President.
PMID: 41101630 DOI: 10.1016/j.jid.2025.09.376
Abstract

Immune checkpoint blockade (ICB) has transformed melanoma therapy but is frequently limited by acquired resistance. Focal adhesion kinase (FAK) and its homolog Pyk2 are non-receptor tyrosine kinases that coordinate cell-matrix adhesion and cytoskeletal signaling. Here, we define the distinct roles of FAK-as the principal scaffold-and PYK2-in a supportive capacity-in IFN-γ-mediated ICB resistance. Label-free phosphoproteomic profiling revealed that IFN-γ stimulation drives extensive phosphorylation across pathways governing cytoskeletal remodeling, transcriptional regulation, mRNA splicing, and rRNA biogenesis. Selective FAK inhibition markedly suppressed IFN-γ-induced STAT1 and PD-L1 upregulation, and the addition of Pyk2 blockade achieved maximal suppression, culminating in enhanced CD8+ T cell-mediated tumor cytotoxicity. In an anti-PD-1-resistant murine melanoma model, high tumoral FAK expression correlated with treatment failure. Analysis of the TCGA-SKCM cohort showed that FAK levels associate with immunosuppressive gene signatures, while in an independent clinical dataset (GSE91061), patients exhibiting post-treatment downregulation of FAK experienced improved outcomes. Single-cell RNA Sequencing distinguished tumor cell-intrinsic FAK expression from Pyk2 enrichment in immune subsets. Together, these data position FAK as the dominant driver of IFN-γ-dependent resistance, with Pyk2 playing a subsidiary role, and suggest that selective FAK targeting-potentially combined with limited Pyk2 inhibition-may overcome ICB resistance in melanoma.

Keywords

FAK; IFN-γ; Immune checkpoint blockade(ICB); PD-L1; melanoma.

Figures
Products