Nano-drug Regulate Tumor Microenvironment To Enhance Immunotherapy

First section:While tumor-infiltrating cytotoxic T lymphocytes play a critical role in controlling tumor development,they are generally impotent in an acidic tumor microenvironment.Systemic treatment to neutralize tumor acidity thus holds promisefor the reversalof the anergic state of T cells and the improvement ofT cell-associated immunotherapy.Herein,we report a proof-of-concept of RNAi nanoparticle-mediated therapeutic reversion of tumor acidity to restore the anti-tumor functions of T cells and potentiate the checkpoint blockade therapy.Our strategy utilized an in vivo optimized vesicular cationic lipid-assisted nanoparticle,as opposed to its micellar counterpart,to mediate systematic knockdown of lactate dehydrogenase A(LDHA)in tumor cells.The treatment resulted in the reprogramming of pyruvate metabolism,a reduction of the production of lactate,and the neutralization of the tumor pH.In immunocompetent syngeneic melanoma and breast tumor models,neutralization of tumor acidity increased infiltration with CD8+T and NK cells,decreased the number of immunosuppressive T cells,and thus significantly inhibited the growth of tumors.Furthermore,the restoration of tumoral pH potentiated checkpoint inhibition therapy using the antibody of programmed cell death protein 1(PD-1).However,in immunodeficient B6/Rag1-/-and NOG mice,the same treatment failed to control tumor growth,further proving that the attenuation of tumor growth by tumor acidity modulation was attributable to the activation of tumor-infiltrating immune cells.Second section:Immunogenic cell death(ICD)plays a pivotal role in cancer immunotherapy due to lead to the activation of potent anticancer immunity.In this work,we demonstrated that second near infrared light-mediated photothermal therapy(PTT)could induce ICD of tumor cells by provoking innate and adaptive immunity,thus preventing cancer metastasis.Specially,photothermal agents(PTAs)of Au-liposome prepared via a facile method exhibit excellent photothermal performance in the first and second near infrared light biowindows(600-1100 nm)precisely tunable LSPR via phase transition temperature control.In vitro cell experiments demonstrated that higher temperature of PTT induced which would promote cells undergoing ICD to express/release much more damage-associated molecular patterns(DAMPs),independent of the wavelength of the irradiation lasers.However,NIR(?)can offer higher tissue-penetration depth than NIR(?)to result in distribution and presence of DAMPs in deeper tumors.ICD induced by NIR(II)activated innate immunity and adaptive immunity mature DCs that facilitate proliferation of interferony(IFN?)-producing CD4+/CD8+ T cells and Natural Killer(NK)cells.Gold standard vaccination experiment confirmed ICD evoked was provided a potent anticancer vaccines in mouse tumor vaccination models.Additionally,ICD induced by NIR(II)combined with imiquimod and checkpoint blockade therapy of ?-PD-1 exerted strikingly therapeutic effective against primary and distant tumors on xenograft 4T1 mouse models.Furthermore,we used a systemic administrated erythrocyte membrane-coated 2D ultrathin polypyrrole nanosheets with NIR(II) to realize a synergistic photothermalimmunological response and tuned to elicit anti,tumor immunity can exert striking therapeutic effects against an artificial whole-body metastasis tumour model with prolonging the survival time of mice.