Ontology highlight
ABSTRACT:
PROVIDER: PRJNA754385 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15443900_1.fastq.gz | Fastqsanger.gz | |||
| SRR15443900_2.fastq.gz | Fastqsanger.gz | |||
| SRR15443901_1.fastq.gz | Fastqsanger.gz | |||
| SRR15443901_2.fastq.gz | Fastqsanger.gz | |||
| SRR15443902_1.fastq.gz | Fastqsanger.gz |
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Project description:Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet acquired immune resistance remains a major barrier to durable response. Here, we identify a previously unrecognized immunometabolic axis in which elevated systemic phenylalanine (Phe) - driven by dietary intake or ICI-induced hepatic dysfunction - promotes immune evasion. Mechanistically, ICI-induced IL-6 and IFN-γ trigger proteasomal degradation of phenylalanine hydroxylase (PAH) via a TOPK-HECTD1 pathway in hepatocytes, leading to increased circulating Phe. Excess Phe suppresses antitumor immunity by impairing STING activation in tumor-associated neutrophils (TANs), through antagonism of glutamate-GRIK1-CaMKIV signaling. We uncover a key STING phosphorylation site (S324/326) essential for ER-to-Golgi trafficking and type I interferon responses, which is disrupted by Phe. These effects are independent of cGAS-cGAMP and define a glutamate-sensing checkpoint in neutrophil immunity. Therapeutically, restoring PAH function using liver-targeted synthetic RNA mimetics of HULC - a noncoding RNA shown to allosterically enhance PAH enzymatic activity - or activating GRIK1 with SYM2081 reprograms the tumor microenvironment, enhances CD8⁺ T cell function, and overcomes ICI resistance. This work reveals hepatic metabolic reprogramming as a central mechanism of immune escape and highlights new therapeutic opportunities to boost immunotherapy efficacy.
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Project description:The efficacy of immunotherapy in prostate cancer is not satisfactory due to the heterogeneity of this cancer, the “cold” tumor microenvironment and the paucity of neoantigens. The STING-TBK1-IRF3 signaling axis as core molecules of the innate immune system is increasingly recognized as a candidate target for cancer immunotherapy. Inhibition of CDK4/6 has been reported to r increase T-cell activation to enhance antitumor immunity. However, little is known about the relationship between CDK4/6 and innate immune-related STING signaling. In this study, we revealed that combination treatment with CDK4/6 inhibitors and STING agonists is significantly more effective than treatment with STING agonists alone in eliminating prostate cancer cells. Then, we demonstrated that CDK4/6 phosphorylate TBK1 at S527 to inactive the STING signaling pathway independent of RB1 in prostate cancer cell. On the other hand, CDK4/6 phosphorylate RB1 at S249/T252 to promote the interaction of RB1 with TBK1 and diminish the phosphorylation of TBK1 at S172, which also suppresses the activation of the STING pathway. Collectively, we found that CDK4/6 inhibits the STING/TBK1/IRF3 axis through RB1-dependent and RB1-independent pathways and elucidated the detailed mechanism. These insights lay a solid foundation for the synergistic application of CDK4/6 inhibitors with STING activators in prostate cancer patients.
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Project description:The biological consequences and mechanisms of metabolic reprogramming of macrophages in the tumor microenvironment (TME) remain largely elusive. Here we showed, in part by myeloid-specific ablation of Sin1, a key component of mammalian target of rapamycin complex (mTORC) 2, that the Sin1-mTORC2-Akt-sterol regulatory element-binding proteins (SREBPs) signaling was augmented in tumor-associated macrophages (TAMs), leading to excessive lipid synthesis and accumulation, which consequently impaired the STING-dependent type I interferon production and CD8+ T cell mediated anti-tumor immunity. The ability of Sin1 deficiency in TAMs to inhibit lipid synthesis and enhance anti-tumor immunity could be blunted by the accumulation of cholesterol/lipids in TAMs. Furthermore, genetic ablation of Sin1 in TAMs or pharmacologic inhibition of lipid anabolism acted synergistically with immune checkpoint blockade (ICB)-based cancer therapy to control tumor growth. Finally, elevated Sin1-mTORC2-Akt activity and lipid anabolism as well as decreased type I IFN responses were all observed in TAMs from human colon cancers and tightly associated with poor patient survival. Together, our study uncovers a novel role of Sin1-regulated lipid anabolic pathway in TAMs which acts as a metabolic checkpoint for anti-tumor immunity via limiting a STING-dependent type I IFN response.
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