Backgound: Although Myeloid-derived suppressor cells (MDSCs) have a prominent ability to suppress the immune responses of T lymphocytes and propel tumor immune escape, a lack of profound systemic immunesuppression in tumor-bearing mice and tumor patients. The underlying mechanism of these remains unclear. Methods: For this purpose, renal cancer-derived exosomes (RDEs) were first labeled with PKH67 and been observed the internalization by MDSCs. Flow cytometry analysis showed the proportion and activity change of MDSCs in spleen and bone marrow induced by RDEs. Further, western blot experiments were used to verify triggered mechanism of MDSCs by RDEs. Finally, proliferation and cytotoxicity of cytotoxic T lymphocytes (CTLs) co-cultured with MDSCs in vitro and a series of experiments in vivo were performed to demonstrate the specific inhibitory effect of RDEs-induced MDSCs. Results: This study suggested that RDEs crucially contributed to presenting antigenic information, activating and driving specific immunosuppressive effect to MDSCs. HSP70, which is highly expressed in RDEs, initiate this process in a toll like receptor 2 (TLR2)-dependent manner. Importantly, RDEs-induced MDSCs could exert an antigen-specific immunosuppression effect on CTL and specific promote renal tumors-growth and immune escape in consequence. Conclusion: The immunosuppression mediated by MDSCs which is induced by RDEs is antigen-specific. HSP70, which is highly expressed in RDEs, plays a pivotal role in this process. Targeted abrogating the function of MDSCs, or eliminating the expression of HSP70 in exosomes, or blocking the crosstalk between them provides a new direction and theoretical support for future immunotherapy. Graphical

Resistance to enzalutamide (Enza) in castration-resistant prostate cancer (CRPC) is linked to poor prognosis. While KDM5B is highly expressed in Enza-resis

Background: To evaluate the relationship between soluble CD36 (sCD36) and type 2 diabetes mellitus complicated by hepatocellular carcinoma (T2DM-HCC), and to explore its potential clinical prognostic value. Methods: A prospective study was conducted enrolling newly diagnosed T2DM-HCC patients from two medical centers, along with control groups including healthy individuals (HC), T2DM patients, and HCC patients. Clinical, biochemical, and pathological data were collected. Serum sCD36 levels were measured by ELISA. Univariate and multivariate analyses were used to identify recurrence risk factors, and ROC analysis was performed to evaluate diagnostic performance. Results: Among 258 participants, the T2DM-HCC group exhibited the highest sCD36 levels, impaired liver function, lower platelets, and mild chronic inflammation. In this group, sCD36 levels positively correlated with tumor stage, size, and proliferation. In univariable analysis, it was associated with postoperative recurrence (OR = 2.57, 95% CI: 0.68– 9.67). The predictive ability of sCD36 for recurrence (AUC = 0.86) was comparable to AFP (AUC = 0.89), while their combination showed the highest accuracy (AUC = 0.94). Conclusion: sCD36 is associated with tumor progression in T2DM-HCC patients and serves as an independent risk factor for recurrence. To the best of our knowledge, this is the first study to identify sCD36 as a critical clinical biomarker for disease progression in T2DM-HCC, with strong potential for clinical application. Trial Registration: This study was registered in September 2024 with the Chinese Clinical Trial Registry (ChiCTR), registration number: ChiCTR2400089651.

Persistent androgen receptor (AR) signaling, metabolic alterations, and changes in the immune microenvironment are contributing factors to the progression of prostate cancer (PCa); however, therapeutic strategies capable of simultaneously targeting these interconnected vulnerabilities remain limited. Here, we identify a combinatorial regimen consisting of dihydroartemisinin and eupatilin (D&E) as a suppressor of PCa progression through coordinated disruption of tumor-intrinsic survival signaling and protumor immune interactions. Functionally, D&E suppressed the proliferation of PCa cells. Mechanistically, D&E induces ferroptosis in PCa cells, as evidenced by lipid peroxidation, intracellular iron accumulation, malondialdehyde elevation, and glutathione reduction. We further identified AR as an important target of D&E and found that it promotes resistance to ferroptosis by sustaining the SLC7A11 antioxidant axis through transcriptional activation of SLC7A11. Upstream, D&E inhibited the NF-κB subunit p65, which transcriptionally maintains AR expression, thus establishing an NF-κB/AR/SLC7A11 signaling cascade underlying ferroptosis resistance in PCa. Beyond tumor-intrinsic effects, D&E also remodels the tumor microenvironment. Specifically, AR-high tumor cells were found to facilitate M2-like macrophage polarization. In turn, M2-like macrophages could secrete SPP1, which potentially augments malignant properties and AR signaling in tumor cells via the CD44 pathway, thereby constituting a protumorigenic positive feedback loop. Notably, D&E attenuated the M2-like phenotype, reduced SPP1 secretion, and reduced macrophage-mediated promotion of PCa proliferation. In immunocompetent mouse models, D&E further synergized with anti-PD-L1 to suppress PCa progression. Together, these findings indicate that D&E exert antitumor effects in PCa by promoting ferroptosis-associated cell death and modulating macrophage-associated microenvironmental signaling, with potential therapeutic relevance particularly in AR-positive PCa.