Correction: SENP3 inhibition suppresses hepatocellular carcinoma progression and improves the efficacy of anti-PD-1 immunotherapy
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SENP3 inhibition suppresses hepatocellular carcinoma progression and improves the efficacy of anti-PD-1 immunotherapy
The importance of SUMOylation in tumorigenesis has received increasing attention, and research on therapeutic agents targeting this pathway has progressed. However, the potential function of SUMOylation during hepatocellular carcinoma (HCC) progression and the underlying molecular mechanisms remain unclear. Here, we identified that SUMO-Specific Peptidase 3 (SENP3) was upregulated in HCC tissues and correlated with a poor prognosis. Multiple functional experiments demonstrated that SENP3 promotes the malignant phenotype of HCC cells. Mechanistically, SENP3 deSUMOylates RACK1 and subsequently increases its stability and interaction with PKCβII, thereby promoting eIF4E phosphorylation and translation of oncogenes, including Bcl2, Snail and Cyclin D1. Additionally, tumor-intrinsic SENP3 promotes the infiltration of tumor-associated macrophages (TAMs) while reducing cytotoxic T cells to facilitate immune evasion. Mechanistically, SENP3 promotes translation of CCL20 via the RACK1 /eIF4E axis. Liver-specific knockdown of SENP3 significantly inhibits liver tumorigenesis in a chemically induced HCC model. SENP3 inhibition enhances the therapeutic efficacy of PD-1 blockade in an HCC mouse model. Collectively, SENP3 plays cell-intrinsic and cell-extrinsic roles in HCC progression and immune evasion by modulating oncogene and cytokine translation. Targeting SENP3 is a novel therapeutic target for boosting HCC responsiveness to immunotherapy.
Targeting of TAMs: can we be more clever than cancer cells?
With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.
A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours
Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.
Exploring metabolic reprogramming in esophageal cancer: the role of key enzymes in glucose, amino acid, and nucleotide pathways and targeted therapies
Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.
Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity
Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally1,2. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours3. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A2 (TXA2). TXA2 acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA2 using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA2 in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.
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