BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy
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TGFβ is essential for the generation of anti-tumor Th9 cells; on the other hand, it causes resistance against anti-tumor
immunity. Despite recent progress, the underlying mechanism reconciling the double-edged effect of TGFβ signaling in Th9-
mediated cancer immunotherapy remains elusive. Here, we find that TGFβ-induced down-regulation of bifunctional
apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFβ signaling and thus
impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFβR1 at K268, which is critical to
activate TGFβ signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFβR1 ubiquitination and Th9
differentiation, thereby inhibiting Th9-mediated cancer immunotherapy. More interestingly, BFAR-overexpressed Th9 cells
exhibit promising therapeutic efficacy to curtail tumor growth and metastasis and promote the sensitivity of anti–PD-1–mediated
checkpoint immunotherapy. Thus, our findings establish BFAR as a key TGFβ-regulated gene to fine-tune TGFβ signaling
that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated
cancer immunotherapy.
提供机构：
中国科学院上海营养与健康研究所
创建时间：
2023-12-05
