CARD11 serves as a therapeutic biomarker for the drug therapies of ccRCC

Background:The incidence of clear cell renal cell carcinoma(ccRCC)is globally high;however,despite the introduction of innovative drug therapies,there remains a lack of effective biomarkers for evaluating treatment response.Recently,Caspase recruiting domain-containing protein 11(CARD11)has garnered attention due to its significant association with tumor development and the immune system.Methods:The expression of CARD11 mRNA and protein in ccRCC were analyzed by public database and immunohistochemistry.The focus of this study is on the epigenomic modifications of CARD11,its expression of ccRCC immunophenotype,and its correlation with response to immunotherapy and targeted therapy.Furthermore,to investigate the mechanism of this molecule’s influence on different biological behaviors of cells,cell tests in vitro have been conducted to observe the impact of its expression level.Results:CARD11 expression was upregulated which may be mainly modified by body methylation and was correlated with poor prognosis in ccRCC.In the tumor microenvironment of ccRCC,CARD11 expression was positively correlated with increased T lymphocyte infiltration and increased expression of inhibitory immune checkpoints.Moreover,ccRCC patients with high CARD11 expression had a better response to immunotherapy and targeted therapy.The knockdown of CARD11 ultimately suppressed the proliferation,migration,and invasion capabilities of ccRCC cells while simultaneously enhancing tumor cell apoptosis.Conclusion:We identified CARD11 as a novel therapeutic biomarker for immunotherapy and targeted therapy in ccRCC.

Folic acid-modified Exosome-PH20 enhances the efficiency of therapy via modulation of the tumor microenvironment and directly inhibits tumor cell metastasis

High accumulation of hyaluronan(HA)in the tumor microenvironment leads to an increase in the interstitial pressure and reduction perfusion of drugs.Furthermore,high molecular-weight(HMW)-HA suppresses M1 macrophage polarization,enhances M2 polarization,and induces immunosuppression.Hyaluronidase treatment have attempted to decrease the quantity of HA in tumors.However,hyaluronidase-driven HA degradation driven accelerates tumor cell metastasis,which is a major cause of mortality in cancer patients.Thus,we designed a novel exosome-based drug delivery system(DDS),named Exos-PH20-FA,using genetic engineering to express human hyaluronidase(PH20)and self-assembly techniques to modify the exosomes with folic acid(FA).Our results show that Exos-PH20-FA degraded HMW-HA to low-molecular-weight(LMW)-HA.Moreover,LMW-HA polarized macrophages to the M1 phenotype and reduced the number of relevant immunosuppressive immunocytes which changed the immune microenvironment from an immunosuppressive to immunosupportive phenotype.Furthermore,we demonstrated Exos-PH20-FA directly reduced hyaluronidase-induced metastasis of tumor cells.This tumor treatment also allowed an enhanced delivery of chemotherapy by tumor-targeting effect with FA modification.Our findings indicate that Exos-PH20-FA improves tumor treatment efficiency and reduces the side effects of hyaluronidase treatment,namely tumor cell metastasis.This all-in-one exosome-based HA targeting DDS maybe a promising treatment that yields more efficient and safer results.