T Cell-Mediated Targeted Delivery Of Tadalafil Regulates Immunosuppression And Polyamine Metabolism To Overcome Immune Checkpoint Blockade Resistance In Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma(HCC)is one of the malignant tumors that seriously endanger the health of people around the world.It is the sixth most common malignant tumor and the third cause of death in the world.The incidence of liver cancer in China ranks the fourth,and the fatality rate ranks the second.Currently,systemic therapy including chemotherapy,immune checkpoint blockade(ICB),tyrosine kinase inhibitors(TKIs),and monoclonal antibodies has significantly improved overall survival and quality of life in HCC patients.In recent years,anti-tumor immunotherapy with immune checkpoint inhibitors(ICI)against PD-1 and PD-L1 has attracted much attention.ICI has been approved in the first-line and second-line treatment of advanced liver cancer,providing new options and hope for patients.However,the objective response rate of ICB monotherapy for HCC is only15-20%,which is related to ICB resistance caused by immunosuppressive tumor microenvironment(TME)and drug discontinuation resulting from immunerelated side effects.Therefore,studying the mechanisms of ICI resistance and seeking effective treatments and reducing immune-related side effects are key to improve the efficacy of HCC.The inhibitory immune microenvironment is one of the important links in the mechanism of immunotherapy resistance in HCC.Thus,novel strategies that can simultaneously reshape immunosuppressive TME and ameliorate side effects are urgently needed.TA is a selective phosphodiesterase(PDE5)inhibitor,mainly used for the treatment of erectile dysfunction(ED),the treatment of pulmonary hypertension(PAH)and improvement of exercise capacity,and the treatment of benign prostatic hyperplasia(BPH).In recent years,studies have found that TA can play the immune regulation function through the regulation of immune microenvironment(MDSCs and Arg 1)and other mechanisms,and enhance the efficacy of immunotherapy.However,the role of TA on the immune microenvironment and metabolism in HCC immunotherapy is still unknown.PurposeTo define the new role of TA in overcoming the immunosuppressive tumor microenvironment and metabolism,and to determine the effect of TA on M2 polarization and polyamine metabolism in tumor-associated macrophages(TAMs)and myeloidderived suppressor cells(MDSCs)was identified.Then,a tumor-targeted drug delivery strategy with dual p H-sensitive nanomedicine carrying both TA and a PD-1was applied to further investigate its role in overcoming ICB resistance and improving the efficacy of immunotherapy.MethodUsing in vitro and in situ HCC models to explore and demonstrate the new role of the clinically conventional drug tadalafil(TA)in overcoming the immunosuppressive tumor microenvironment.To determine the effects of TA on M2 polarization and polyamine metabolism in tumor-associated macrophages(TAMs)and bone marrow-derived suppressor cells(MDSCs).After clarifying the above immunomodulatory effects of TA,we introduced a nanomedicine-based tumor-targeted drug delivery strategy to better utilize TA to reverse immunosuppressive TME and overcome ICB resistance for HCC immunotherapy.We developed a dual p H-sensitive nanomedicine carrying both TA and programmed cell death receptor 1 antibodies(a PD-1)and evaluated its ability for tumor-targeted drug delivery and TME-responsive drug release in an orthotopic HCC model.Finally,we analyzed the immunomodulatory effects,anti-tumor therapeutic effects,and side effects of dual p H-sensitive nanodrugs carrying both TA and a PD-1.Results1 TA reverses the immunosuppressive TME and reactivating CD8 + T cells by inhibiting M2 polarization and polyamine metabolismin TAMs and MDSCs.2 A dual p H-sensitive nanodrug was successfully synthesized to simultaneously carry both TA and a PD-1 with good stability and low toxicity.3 Nanodrugs provide both TA and a PD-1,multipathway and synergistic regulation of TME.4 Nanodrugs improves the therapeutic efficacy of HCC with low side effects.ConclusionOur novel tumor-targeted nanodrugs co-deliver TA and a PD-1,utilized TA to reverse immunosuppressive TME,overcome ICB resistance,and improved the therapeutic efficacy of HCC with low side effects.Expands the application of TA in tumor therapy and holds great potential to break the logjam of ICB-based HCC immunotherapy.