ArticleProceedings of the National Academy of Sciences of the United States of America2025
TMEM16F phospholipid scramblase regulates tumorigenesis by modulating the tumor immune microenvironment.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
5 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Evaluation of translational potential of mRNA vaccine candidate antigens for pancreatic cancer: a systematic review based on clinical evidence and stratified prioritization strategies.Frontiers in immunology · 2026Pooled it
- Lipid flip-flop in biological membranes: through the lens of TMEM16F.Physiological reviews · 2026Review
- Recent advances in TMEM16F: structural plasticity, functional versatility, and implications for human diseases.Cell communication and signaling : CCS · 2026Review
- Tumor cell intrinsic mechanisms of immune escape.Cell communication and signaling : CCS · 2026Review
- TMEM16F phospholipid scramblase regulates tumorigenesis by modulating the tumor immune microenvironment.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
The immunosuppressive tumor microenvironment enables immune evasion through mechanisms beyond canonical immune checkpoints. While phosphatidylserine (PS) externalization coordinates apoptotic clearance under physiological conditions, tumors hijack this mechanism through apoptotic mimicry to subvert antitumor immunity. Here, we identify TMEM16F, a calcium-activated phospholipid scramblase, as a driver of tumor-intrinsic PS externalization. TMEM16F-mediated PS scrambling polarized macrophages to an immunosuppressive M2 phenotype, which promotes TGF-β1 secretion and regulatory T cell expansion to suppress cytotoxic lymphocytes. Genetic ablation of TMEM16F abolished PS exposure, systemically reprogrammed the tumor microenvironment and primary immune organs toward immune activation, and suppressed tumor growth across cancer models. Pharmacological scramblase inhibition produced these effects, demonstrating therapeutic potential. Our findings establish TMEM16F-dependent phospholipid scrambling as a critical immune evasion axis and propose targeting this pathway for cancer treatment.
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Registered trials
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