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.
Gut microbiota as a new target for anticancer therapy: from mechanism to means of regulation
In order to decipher the relationship between gut microbiota imbalance and cancer, this paper reviewed the role of intestinal microbiota in anticancer therapy and related mechanisms, discussed the current research status of gut microbiota as a biomarker of cancer, and finally summarized the reasonable means of regulating gut microbiota to assist cancer therapy. Overall, our study reveals that the gut microbiota can serve as a potential target for improving cancer management.
A multifunctional mesoporous silica drug delivery nanosystem that ameliorates tumor hypoxia and increases radiotherapy efficacy
Radiotherapy (RT) is a widely used treatment with strong therapeutic effects, but overcoming challenges related to hypoxia-induced tumor resistance and ineffective antitumor immune responses is crucial for optimal outcomes. In this study, we developed a versatile nanosystem using mesoporous silica nanoparticles (MSNs), R837, and a small quantity of manganese peroxide (Mn/ZnO2). The synthesized MSN@R837-Mn/ZnO2 nanoparticles exhibited precise tumor targeting and accumulation, controlled drug release under acidic conditions, and increased sensitivity in magnetic resonance imaging. These attributes collectively augmented the therapeutic efficacy of RT by alleviating hypoxia and immunosuppression. Tumor cells treated with RT combined with these nanoparticles displayed reduced oxidative stress, alleviated hypoxia, and normalized blood vessel formation. Notably, all mice in the RT + PD-1 + MSN@R837-Mn/ZnO2 group achieved complete tumor regression with extended survival. Safety assessments confirmed the absence of MSN@R837-Mn/ZnO2 toxicity, highlighting its potential as a promising approach with dual functionality for the diagnostic imaging and treatment of cancer.
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.
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