Qingchen Zhu

Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.

Ubiquitination is an essential mechanism in the control of antiviral immunity upon virus infection. Here, we identify a series of ubiquitination-modulating enzymes that are modulated by vesicular stomatitis virus (VSV). Notably, TRIM24 is down-regulated through direct transcriptional suppression induced by VSV-activated IRF3. Reducing or ablating TRIM24 compromises type I IFN (IFN-I) induction upon RNA virus infection and thus renders mice more sensitive to VSV infection. Mechanistically, VSV infection induces abundant TRIM24 translocation to mitochondria, where TRIM24 binds with TRAF3 and directly mediates K63-linked TRAF3 ubiquitination at K429/K436. This modification of TRAF3 enables its association with MAVS and TBK1, which consequently activates downstream antiviral signaling. Together, these findings establish TRIM24 as a critical positive regulator in controlling the activation of antiviral signaling and describe a previously unknown mechanism of TRIM24 function.

Abstract Background Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy. However, the unique features of the immune microenvironment of triple negative breast cancer (TNBC) compared with other subtypes of breast cancer remain elusive. Therefore, we aimed to depict and compare the immune landscape among TNBC, human epidermal growth factor receptor 2‐positive (HER2 + ) breast cancer, and luminal‐like breast cancer. Methods Single‐cell RNA sequencing (scRNA‐seq) was performed on CD45 + immune cells isolated from human normal breast tissues and primary breast tumors of various subtypes. By analyzing the scRNA‐seq data, immune cell clusters were identified and their proportions as well as transcriptome features were compared among TNBC, human HER2 + breast cancer, and luminal‐like breast cancer. Pseudotime and cell‐cell communication analyses were also conducted to characterize the immune microenvironment. Results ScRNA‐seq data of 117,958 immune cells were obtained and 31 immune clusters were identified. A unique immunosuppressive microenvironment in TNBC was decoded as compared to that in HER2 + or luminal‐like breast cancer, which was characterized by higher proportions of regulatory T cells (Tregs) and exhausted CD8 + T cells and accompanied by more abundant plasma cells. Tregs and exhausted CD8 + T cells in TNBC exhibited increased immunosuppression signature and dysfunctional scores. Pseudotime analyses showed that B cells tended to differentiate to plasma cells in TNBC. Cell‐cell communication analyses indicated that these unique features are fostered by the diversified T cell‐B cell crosstalk in TNBC. Based on the T cell‐B cell crosstalk, a prognostic signature was established that could effectively predict the prognosis status for patients with TNBC. Additionally, it was found that TNBC had a higher proportion of cytotoxic natural killer (NK) cells, whereas HER2 + or luminal‐like breast cancer lost this feature, suggesting that HER2 + or luminal‐like breast cancer, but not TNBC, may benefit from NK‐based immunotherapy. Conclusions This study identified a distinct immune feature fostered by T cell‐B cell crosstalk in TNBC, which provides better prognostic information and effective therapeutic targets for breast cancer.