TMEM16F phospholipid scramblase regulates tumorigenesis by modulating the tumor immune microenvironment

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Tumor microenvironments create immunosuppression beyond immune checkpoints.
• Tumors exploit phosphatidylserine (PS) externalization, a process normally for apoptotic clearance, to evade immune detection via apoptotic mimicry.

Purpose of the Study:

• To identify the molecular mechanisms driving tumor-intrinsic PS externalization.
• To investigate the role of TMEM16F in tumor-associated immunosuppression.
• To evaluate TMEM16F inhibition as a potential cancer therapy.

Main Methods:

• Identified TMEM16F as a calcium-activated phospholipid scramblase responsible for PS exposure.
• Utilized genetic ablation of TMEM16F in cancer models.
• Administered pharmacological TMEM16F inhibitors.
• Analyzed immune cell polarization (macrophages, T cells) and cytokine profiles (TGF-β1).
• Assessed tumor growth and immune status in primary immune organs.

Main Results:

• TMEM16F drives tumor-intrinsic PS externalization, polarizing macrophages to an immunosuppressive M2 phenotype.
• M2 macrophages promote TGF-β1 secretion and regulatory T cell expansion, suppressing cytotoxic lymphocytes.
• Genetic or pharmacological inhibition of TMEM16F abolished PS exposure.
• TMEM16F ablation led to systemic immune activation in tumors and immune organs.
• Suppression of tumor growth was observed across multiple cancer models upon TMEM16F targeting.

Conclusions:

• TMEM16F-dependent phospholipid scrambling is a key mechanism of immune evasion in cancer.
• Targeting TMEM16F reverses tumor-induced immunosuppression and activates antitumor immunity.
• Inhibiting TMEM16F represents a promising therapeutic strategy for cancer treatment.