Engineering Nanosensitizer to Remodel the TME for Hypoimmunogenic "Cold"-"Hot" Tumor Transformations.

α-PD-L1 therapy has shown encouraging results at harnessing the immune system to combat cancer. However, the treatment effect is relatively low due to the dense extracellular matrix (ECM) and tumor immunosuppressive microenvironment (TIME). Therefore, an ultrasound (US)-responsive nanosensitizer (URNS) is engineered to deliver losartan (LST) and polyethylenimine (PEI) to remolde the TME, driving "cold"-"hot" tumor transformation and enhancing the sensitivity of α-PD-L1 therapy. In the tumor site, noninvasive US can make MTNP generate ROS, which cleave ROS-sensitive bonds to dissociate MTNPtK@LST-PEI, shedding PEI and releasing LST from mesoporous spheres. The results demonstrated that URNS combined with α-PD-L1 therapy effectively inhibited tumor growth with an inhibition rate as high as 90%, which was 1.7-fold higher than that of the α-PD-L1 treatment in vivo. In summary, the URNS improves the sensitivity of α-PD-L1 therapy by remodeling the TME, which provides promising insights for optimizing cancer immunotherapy.

Menin-MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers.

Encoded by the MEN1 gene, menin protein is a fusion protein that is essential for the oncogenic transformation of mixed-lineage leukemia (MLL) and leads to acute leukemia (AL). Therefore, accumulating evidence has demonstrated that inhibition of the high-affinity relationship between menin and mixed-lineage leukemia 1 (MLL1 and KMT2A) is an effective treatment for MLL-rearranged (MLL-r) leukemia in vitro and in vivo. Meanwhile, recent studies found that menin-MLL1 interaction inhibitors exhibited a firm tumor suppressive ability in specific cancer cells, such as prostate cancer, breast cancer, liver cancer, and lung cancer. Overall, it seems to serve as a novel therapeutic means for cancers. Herein, we review the recent progress in exploring the inhibitors of small molecule menin-MLL1 interactions. The molecular mechanisms of these inhibitors' functions and their application prospects in the treatment of AL and cancers are explored.

A Self-Disguised Nanospy for Improving Drug Delivery Efficiency via Decreasing Drug Protonation.

Nanoscale drug carriers play a crucial role in reducing side effects of chemotherapy drugs. However, the mononuclear phagocyte system (MPS) and the drug protonation after nanoparticles (NPs) burst release still limit the drug delivery efficiency. In this work, a self-disguised Nanospy is designed to overcome this problem. The Nanospy is composed of: i) poly (lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) loading doxorubicin is the core structure of the Nanospy. ii) CD47 mimic peptides (CD47p) is linked to NPs which conveyed the "don't eat me" signal. iii) 4-(2-aminoethyl) benzenesulfonamide (AEBS) as the inhibitor of Carbonic anhydrase IX (CAIX) linked to NPs. Briefly, when the Nanospy circulates in the bloodstream, CD47p binds to the regulatory protein α (SIRPα) on the surface of macrophages, which causes the Nanospy escapes from phagocytosis. Subsequently, the Nanospy enriches in tumor and the AEBS reverses the acidic microenvironment of tumor. Due to above characteristics, the Nanospy reduces liver macrophage phagocytosis by 25% and increases tumor in situ DOX concentration by 56% compared to PLGA@DOX treatment. In addition, the Nanospy effectively inhibits tumor growth with a 63% volume reduction. This work presents a unique design to evade the capture of MPS and overcomes the influence of acidic tumor microenvironment (TME) on weakly alkaline drugs.

Pyroptosis-Related Subtypes Predict the Response of Clear Cell Renal Cell Carcinoma to Targeted Therapy.

BACKGROUND: Pyroptosis plays a crucial role in anti-tumor immunity and in formation of the immune microenvironment. However, whether pyroptosis is involved in the progression of clear cell renal cell carcinoma (ccRCC) is still unclear. Personalized treatment of ccRCC requires detailed molecular classification to inform a specific therapy. METHODS: Molecular subtyping of ccRCC was performed based on consensus clustering of pyroptosis-related genes. The characteristics of these molecular subtypes were explored at the genome, transcriptome and protein levels. Single-cell RNA sequencing and CIBERSORT analysis were used to analyse the immune microenvironment of ccRCC, while Lasso regression was used to develop a prediction model based on hub genes. Expression of the pyroptosis-related gene GSDMB was also investigated at the tissue and cellular levels. RESULTS: Two molecular subtypes were identified based on the clustering of pyroptosis-related genes. Cluster 1 was associated with activation of classical oncogenic pathways, especially the angiogenesis pathway. Cluster 2 was associated with activation of immune-related pathways and high levels of immunosuppressive cells, exhausted CD8+ T cells, and tumor-associated fibroblast infiltration. Clusters 1 and 2 were thus defined as the angiogenic and inflamed subtypes, respectively. The two subtypes were predictive of the response of ccRCC to anti-angiogenic therapy and immunotherapy, with Cluster 1 patients benefiting from anti-angiogenic therapy and Cluster 2 patients showing better response to anti-PD1 inhibitor therapy. Furthermore, a 9-gene expression signature (HJURP, NUF2, KIF15, MELK, TPX2, PLK1, CDCA3, CTLA4, FOXP3) was identified that could predict outcome and response to immune checkpoint blockade therapy in test cohorts. Finally, GSDMB was found to be involved in the development of renal clear cell carcinoma. CONCLUSIONS: These results on pyroptosis-related genes in ccRCC provide a theoretical basis for understanding molecular heterogeneity and for the development of individualized treatment strategies.

PTEN loss promotes Warburg effect and prostate cancer cell growth by inducing FBP1 degradation.

Rationale: Fructose-1,6-bisphosphatase (FBP1) is a tumor suppressor and a key enzyme negatively regulating Warburg effect in cancer. However, regulation of FBP1 protein expression and its exact role in prostate cancer (PCa) is largely unclear. Phosphatase and tensin homolog (PTEN) is one of the most frequently deleted tumor suppressor genes in human PCa. However, the role of PTEN loss in aberrant Warburg effect in cancer remains poorly understood. Methods: Expression of PTEN and FBP1 was analyzed in several PCa cell lines and prostate tumor tissues in mice. Western blot (WB) and RT-PCR approaches were used to examine how PTEN regulates FBP1 expression. Co-immunoprecipitation (co-IP) and in vivo ubiquitination assays were used to define the regulatory mechanisms. A PCa xenograft model was employed to determine the impact of PTEN regulation of FBP1 on PCa growth in vivo. Result: We demonstrated that in a manner dependent of PI3K/AKT signal pathway PTEN regulated FBP1 expression in various PCa cell lines and tumors in mice. We confirmed that this regulation took place at the protein level and was mediated by SKP2 E3 ubiquitin ligase. Mechanistically, we showed that serine 271 phosphorylation of FBP1 by cyclin-dependent kinases (CDKs) was essential for SKP2-mediated degradation of FBP1 protein induced by PTEN loss. Most importantly, we further showed that loss of PTEN expression enhanced Warburg effect and PCa growth in mice in a manner dependent, at least partially on FBP1 protein degradation. Conclusions: Our results reveal a novel tumor-suppressive feature of PTEN in restraining FBP1 degradation and the Warburg effect. These results also suggest that prohibiting FBP1 protein degradation could be a viable therapeutic strategy for PTEN-deficient PCa.

Transformable ECM Deprivation System Effectively Suppresses Renal Cell Carcinoma by Reversing Anoikis Resistance and Increasing Chemotherapy Sensitivity.

Extracellular matrix (ECM) is crucial in various biological functions during tumor progression, including induction of anoikis resistance and cell adhesion-mediated drug resistance (CAM-DR). Fibronectin (FN) is a vital ECM component with direct regulatory effects on ECM-mediated anoikis resistance and CAM-DR, making it an attractive and innovative therapeutic target for depriving ECM in tumor tissue. Herein, an ECM deprivation system (EDS) is developed based on FN targeting self-assembly peptide for constructing nanofibers in the ECM of renal cell carcinoma (RCC), which contributes to: i) targeting and recognizing FN to form nanofibers for long-term retention in ECM, ii) reversing anoikis resistance via arresting the FN signaling pathway, and iii) serving as a drug-loading platform for sensitizing chemotherapy by ameliorating CAM-DR. The results reveal that EDS significantly reverses anoikis resistance of RCC cells by inhibiting the phosphorylation of FAK, a positive regulator of the FN signaling pathway. Meanwhile, EDS serves as a chemotherapy-sensitizer of cancer, exerting significant synergistic effects with doxorubicin (DOX). In vivo validation experiments show that EDS effectively suppresses metastasis and tumor growth with chemotherapy resistance. Collectively, the innovative EDS notably inhibits the tumor-promoting effect of ECM and may provide a novel approach for suppressing ECM and enhancing chemo-drug sensitivity.

An Ultrasound-Induced Self-Clearance Hydrogel for Male Reversible Contraception.

Nearly half of pregnancies worldwide are unintended mainly due to failure of contraception, resulting in negative effects on women's health. Male contraception techniques, primarily condoms and vasectomy, play a crucial role in birth control, but cannot be both highly effective and reversible at the same time. Herein, an ultrasound (US)-induced self-clearance hydrogel capable of real-time monitoring is utilized for in situ injection into the vas deferens, enabling effective contraception and noninvasive recanalization whenever needed. The hydrogel is composed of (i) sodium alginate (SA) conjugated with reactive oxygen species (ROS)-cleavable thioketal (SA-tK), (ii) titanium dioxide (TiO2), which can generate a specific level of ROS after US treatment, and (iii) calcium chloride (CaCl2), which triggers the formation of the hydrogel. For contraception, the above mixture agents are one-time injected into the vas deferens, which can transform from liquid to hydrogel within 160 s, thereby significantly physically blocking the vas deferens and inhibiting movability of sperm. When fertility is needed, a noninvasive remedial ultrasound can make TiO2 generate ROS, which cleaves SA-tK to destroy the network of the hydrogel. Owing to the recanalization, the refertility rate is restored to 100%. Meanwhile, diagnostic ultrasound (D-US, 22 MHz) can monitor the occlusion and recanalization process in real-time. In summary, the proposed hydrogel contraception can be a reliable, safe, and reversible male contraceptive strategy that addresses an unmet need for men to control their fertility.

Enhanced inflammatory and T-helper-1 type responses but suppressed lymphocyte proliferation in patients with seasonal affective disorder and treated by light therapy.

BACKGROUND: Animals show seasonal changes in the endocrine and immune system in response to winter stressors. Even though increased inflammation has been implicated in the pathophysiology of depression, whether immune disorder is a key mediator in seasonal affective depression (SAD) is unknown. Here, we hypothesized that short photoperiods in winter may induce inflammatory response, which contributes to SAD, and that light treatments should normalize immune function and improve depressive symptoms. METHODS: Twenty patients with a diagnosis of SAD, and a score on the HAM-29 of 20 or higher were recruited for this study. Twenty-one healthy subjects with no personal and family history of psychiatric disorder were matched to patients according to age and sex. Patients and controls were sampled during winter between November and January, inclusive. A subset of SAD patients (N=13) was re-sampled after 4 weeks of light therapy. Blood samples were assayed for macrophage activity, lymphocyte proliferation and cytokine release. RESULTS: SAD patients showed significantly higher macrophage activity and lower lymphocyte proliferation in winter compared to healthy subjects. The concentrations of macrophage-produced proinflammatory cytokines interleukin-1ß and tumour necrosis factor-α, and T-helper (Th)-1 produced cytokine, interferon-γ were all significantly increased. In contrast, no significant changes in Th2-produced cytokines were observed. Light therapy significantly improved depressive scores, which was associated with attenuation of decreased lymphocyte functions, increased macrophage activity and level of proinflammatory cytokines. CONCLUSION: SAD patients have increased macrophage and Th1 type responses in winter, and light therapy normalized immune functions and depressive symptoms. These results support an inflammatory hypothesis for SAD and an immunomodulatory role of light therapy.

Omega-3 fatty acid ethyl-eicosapentaenoate attenuates IL-1beta-induced changes in dopamine and metabolites in the shell of the nucleus accumbens: involved with PLA2 activity and corticosterone secretion.

Previously, we have reported that interleukin-1 beta (IL-1) induces changes in dopaminergic (DA) and serotonergic systems in the core of the [corrected] nucleus accumbens (NAc). We have also demonstrated that n-3 fatty acid ethyl-eicosapentaenoate (EPA) can significantly reduce stress and anxiety-like behaviors, corticosterone concentrations [corrected] and peripheral inflammatory response induced by IL-1 administration. Compared to the core, the shell is involved more in emotion, stress and psychiatric diseases. However, the relationship between inflammation and the functions of DA system in the shell has not been studied. Since phospholipase (PL) A2 is a key enzyme in the [corrected] arachidonic acid-eicosanoids-prostaglandin [corrected] (PG)E2 pathway, and the change in NAc DA [corrected] system has been associated with glucocorticoid stimulation; [corrected] therefore, the hypotheses of this study are (1) that IL-1 induced changes in DA neurotransmission in the shell may be through PLA2-PGE2-corticosterone pathway; (2) EPA may attenuate IL-1 effects via inhibiting PLA2 activities, which blocks PGE2 stimulation of corticosterone. Using an in vivo microdialysis method, the present study showed that IL-1 administration significantly increased extracellular levels of DA, and its metabolites 3,4-dihydroxyphenylacetic acid, [corrected] and homovanillic acid [corrected] in the shell of the NAc. IL-1 also increased blood concentration of corticosterone and PGE2, and increased the activities of cytosolic and secretory [corrected] PLA2. IL-1-induced changes were significantly attenuated by EPA treatment. Furthermore, glucocorticoid [corrected] receptor antagonist mifepristone (RU486) pretreatment significantly blocked IL-1-induced changes in DA and metabolites. Quinacrine, [corrected] a PLA2 antagonist significantly blocked IL-1-induced [corrected] increase in PGE2 and corticosterone concentrations. These results demonstrated the hypotheses that IL-1 effects may be via PLA2-PGE2-corticosterone pathway and EPA attenuated IL-1 effects may be through the suppression of PLA2 expression, which then reduced PGE2 synthesis and corticosterone secretion.