Mitochondrial NDUFA4 is a functional switch controlling TAMs and tumor immunity (scRNA-Seq)
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PROVIDER: PRJNA1123719 | ENA |
REPOSITORIES: ENA
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Project description:Tumor-associated macrophages (TAMs) play a critical role in the clinical outcome of solid tumors and the efficacy of immune checkpoint blockade (ICB) therapies. Interferon (IFN)-TAMs are a potent anti-tumor TAM subset recently identified in several human cancers, with higher frequencies strongly predicting improved overall survival and ICB responses. Yet the molecular mechanisms governing IFN-TAM gene expression programs and population dynamics remain largely unknown. Herein, we uncover a mitochondrial process where NDUFA4, a subunit of Complex IV of the electron transport chain, serves as a switch that controls TAM functions and tumor immunity. We demonstrate that in response to interferons (IFNs) within the tumor microenvironment, NDUFA4 is dramatically downregulated in TAMs by the cooperative activity of the NDUFA4 homolog NDUFA4L3 and the microRNA miR-147, both encoded by a single highly conserved bifunctional transcript. Notably, repression of NDUFA4 is necessary for the expansion of IFN-TAMs and subsequent anti-tumor immunity via NK and CD8+ T cell recruitment, whereas constitutive NDUFA4 expression supports pro-tumoral TAMs. Unexpectedly, we find that NDUFA4 minimally contributes to mitochondrial respiration but instead primarily functions as a gatekeeper of mitochondrial DNA (mtDNA) release into the cytoplasm. Consequently, NDUFA4 repression enhances mtDNA-induced stimulator of interferon genes (STING) activation, thereby amplifying anti-tumor IFN-induced transcriptional programs in TAMs. Finally, leveraging the exceptional specificity of miR-147 for Ndufa4 mRNA, we demonstrate that RNA-based therapeutics targeting this functional switch enhance ICB efficacy and inhibit tumor growth. In summary, we uncover that tumor microenvironmental cues control the abundance of IFN-TAMs and subsequent anti-tumor immunity through the regulation of NDUFA4 and that this novel functional switch can be exploited for cancer immunotherapies.
2025-06-30 | GSE269804 | GEO
Project description:Tumor-associated macrophages (TAMs) play a critical role in the clinical outcome of solid tumors and the efficacy of immune checkpoint blockade (ICB) therapies. Interferon (IFN)-TAMs are a potent anti-tumor TAM subset recently identified in several human cancers, with higher frequencies strongly predicting improved overall survival and ICB responses. Yet the molecular mechanisms governing IFN-TAM gene expression programs and population dynamics remain largely unknown. Herein, we uncover a mitochondrial process where NDUFA4, a subunit of Complex IV of the electron transport chain, serves as a switch that controls TAM functions and tumor immunity. We demonstrate that in response to interferons (IFNs) within the tumor microenvironment, NDUFA4 is dramatically downregulated in TAMs by the cooperative activity of the NDUFA4 homolog NDUFA4L3 and the microRNA miR-147, both encoded by a single highly conserved bifunctional transcript. Notably, repression of NDUFA4 is necessary for the expansion of IFN-TAMs and subsequent anti-tumor immunity via NK and CD8+ T cell recruitment, whereas constitutive NDUFA4 expression supports pro-tumoral TAMs. Unexpectedly, we find that NDUFA4 minimally contributes to mitochondrial respiration but instead primarily functions as a gatekeeper of mitochondrial DNA (mtDNA) release into the cytoplasm. Consequently, NDUFA4 repression enhances mtDNA-induced stimulator of interferon genes (STING) activation, thereby amplifying anti-tumor IFN-induced transcriptional programs in TAMs. Finally, leveraging the exceptional specificity of miR-147 for Ndufa4 mRNA, we demonstrate that RNA-based therapeutics targeting this functional switch enhance ICB efficacy and inhibit tumor growth. In summary, we uncover that tumor microenvironmental cues control the abundance of IFN-TAMs and subsequent anti-tumor immunity through the regulation of NDUFA4 and that this novel functional switch can be exploited for cancer immunotherapies.
2025-06-30 | GSE269803 | GEO
Project description:Mitochondrial NDUFA4 is a functional switch controlling TAMs and tumor immunity (RNA-Seq)
| PRJNA1123720 | ENA
Project description:Tumor-associated macrophages (TAMs) are major players in regulating the immunosuppressive tumor environment, and their abundance is highly correlated with poor clinical outcomes. Here, we constructed a TAM regulatory network by integrating scRNA-seq data across human solid tumors with a dedicated CRISPR knockout screen. Using a deep generative model capable of learning a local representation for each candidate regulator, we constructed a gene perturbation network that linked individual target genes with prototypical functional modules in TAMs. We identified non-redundant pathways regulating distinct TAM functions, showing modular circuitry. For instance, the complement module is repressed by Stat6, Zeb2, Gpnmb, and Spp1, while the Tgfbr1-Smad2/4 pathway induces this program in TAMs. Importantly, we identified Zeb2 as the master regulator of pro-tumor functions in TAMs, orchestrating the suppression of type I interferon response and antigen presentation alongside the activation of immune suppression programs. Genetic ablation of Zeb2 reprogrammed TAMs identity on chromatin, RNA, and protein levels. In human tumors with high macrophage content, ZEB2 expression was associated with poor prognosis in solid cancers, including lung and bladder. Functional macrophage coculturing assays defined Zeb2 as a critical regulator of TAM immunosuppression activity by inhibiting T cell proliferation and activation. Selective in vivo targeting of Zeb2 in macrophages using a CpGsiRNAZeb2 DNA hybrid reprogrammed TAMs and mobilized systematic anti-tumoral T cell responses, achieving complete tumor clearance as a monotherapy. Overall, our study generated a detailed genetic roadmap of TAM gene circuits and identified ZEB2 as a master switch of TAMs with potential therapeutic implications for macrophage-based immunotherapies.
2025-03-10 | GSE269188 | GEO
Project description:Tumor-associated macrophages (TAMs) are major players in regulating the immunosuppressive tumor environment, and their abundance is highly correlated with poor clinical outcomes. Here, we constructed a TAM regulatory network by integrating scRNA-seq data across human solid tumors with a dedicated CRISPR knockout screen. Using a deep generative model capable of learning a local representation for each candidate regulator, we constructed a gene perturbation network that linked individual target genes with prototypical functional modules in TAMs. We identified non-redundant pathways regulating distinct TAM functions, showing modular circuitry. For instance, the complement module is repressed by Stat6, Zeb2, Gpnmb, and Spp1, while the Tgfbr1-Smad2/4 pathway induces this program in TAMs. Importantly, we identified Zeb2 as the master regulator of pro-tumor functions in TAMs, orchestrating the suppression of type I interferon response and antigen presentation alongside the activation of immune suppression programs. Genetic ablation of Zeb2 reprogrammed TAMs identity on chromatin, RNA, and protein levels. In human tumors with high macrophage content, ZEB2 expression was associated with poor prognosis in solid cancers, including lung and bladder. Functional macrophage coculturing assays defined Zeb2 as a critical regulator of TAM immunosuppression activity by inhibiting T cell proliferation and activation. Selective in vivo targeting of Zeb2 in macrophages using a CpGsiRNAZeb2 DNA hybrid reprogrammed TAMs and mobilized systematic anti-tumoral T cell responses, achieving complete tumor clearance as a monotherapy. Overall, our study generated a detailed genetic roadmap of TAM gene circuits and identified ZEB2 as a master switch of TAMs with potential therapeutic implications for macrophage-based immunotherapies.
2025-03-10 | GSE269191 | GEO
Project description:Tumor-associated macrophages (TAMs) are major players in regulating the immunosuppressive tumor environment, and their abundance is highly correlated with poor clinical outcomes. Here, we constructed a TAM regulatory network by integrating scRNA-seq data across human solid tumors with a dedicated CRISPR knockout screen. Using a deep generative model capable of learning a local representation for each candidate regulator, we constructed a gene perturbation network that linked individual target genes with prototypical functional modules in TAMs. We identified non-redundant pathways regulating distinct TAM functions, showing modular circuitry. For instance, the complement module is repressed by Stat6, Zeb2, Gpnmb, and Spp1, while the Tgfbr1-Smad2/4 pathway induces this program in TAMs. Importantly, we identified Zeb2 as the master regulator of pro-tumor functions in TAMs, orchestrating the suppression of type I interferon response and antigen presentation alongside the activation of immune suppression programs. Genetic ablation of Zeb2 reprogrammed TAMs identity on chromatin, RNA, and protein levels. In human tumors with high macrophage content, ZEB2 expression was associated with poor prognosis in solid cancers, including lung and bladder. Functional macrophage coculturing assays defined Zeb2 as a critical regulator of TAM immunosuppression activity by inhibiting T cell proliferation and activation. Selective in vivo targeting of Zeb2 in macrophages using a CpGsiRNAZeb2 DNA hybrid reprogrammed TAMs and mobilized systematic anti-tumoral T cell responses, achieving complete tumor clearance as a monotherapy. Overall, our study generated a detailed genetic roadmap of TAM gene circuits and identified ZEB2 as a master switch of TAMs with potential therapeutic implications for macrophage-based immunotherapies.
2025-03-10 | GSE269187 | GEO
Project description:Tumor-associated macrophages (TAMs) are a major component of the leukocyte and a heterogenous population in tumors. Recent reports have increasingly suggested that manipulating the function of TAMs may serve as a promising therapeutic strategy against advanced tumors. Our present work indicates that CSF-1R+ TAMs are abundantly found in a significant proportion of COAD specimens. Therefore，to determine the role of the CSF-1Rhigh TAMs in COAD, we sorted the CSF-1Rhigh TAMs and the CSF-1R low TAMs from the colon adenocarcinomas for Smart-seq2. We found that CSF-1Rhigh TAM infiltration involved in multiple tumor immune signaling pathways. CSF-1Rhigh TAMs mostly exhibited a immunosuppressive phenotypes, and were associated with enhanced levels of Treg cells. CSF-1R high TAMs promotes COAD progression by modulating tumor immunity environment
2022-03-31 | GSE193814 | GEO
Project description:Chemotherapies have been shown to enhance anti-tumor immunity, but whether chemotherapies affect tumor-associated macrophages (TAMs) is still uclear. We found TAMs is different before and after chemotherapy by comparing RNA profile of TAMs before and after chemotherapy.
2021-02-16 | GSE134600 | GEO
Project description:ZEB2 is a Master Switch Controlling the Tumor-Associated Macrophage Program
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| PRJNA1107198 | ENA