An Autophagy Cascade Based Nano Platform For Anti-Tumor Immune Enhancement

Based on the synergy of tumor microenvironment,the combination of chemotherapy and immunotherapy is a potential strategy in cancer treatment.Chemoimmunotherapy,low-dose chemotherapy drugs can induce immunogenic death(ICD)of tumor cells,or stimulate tumor-specific immune response through immune mechanism.However,due to the low immunogenicity of tumor and insufficient presentation of tumor endogenous antigen,the stimulation of immune response is weak.At the same time,chemotherapy drugs will cause the body’s self-protection mechanism,and help other tumor cells grow by clearing damaged cell components.This mild autophagy will cause drug resistance of tumor cells.In order to break through the limitations of the low efficiency of chemoimmunotherapy and the tumor microenvironment of immunosuppression,a nano anti-tumor immune enhancement platform(CS-3BP/PA@DOX)based on autophagy cascade was proposed for the first time.Firstly,polymer PS-ASP(ProtamineAutophagy Sensitive Peptide)with pH sensitivity and autophagy enzyme sensitivity were constructed,and DOX(Doxorubicin)was loaded onto polymer PS-ASP through hydrophobic interaction and π-π stacking,forming nanoparticles(PA@DOX),and CS3BP(Chondroitin Sulfate-3-Bromopyruvate)coated to form CS-3BP/PA@DOX nanoparticles with round appearance and uniform particle size.Secondly,using 4T1 cells and Balb/c mice as models,we tested the anti-tumor effect of CS-3BP/PA@DOX in vivo and in vitro,and its mechanism was explained from the perspective of transcriptome analysis.The results indicate that nanoparticles can accumulate at the tumor site through passive targeting of EPR effect and active targeting mediated by CD44 receptor after intravenous injection.Mild cell autophagy mediated by 3BP stimulates the release of DOX,achieving cascade drug release and reducing drug toxicity and side effects.In vivo,3BP can reduce the energy supply of tumor cells by inhibiting glycolysis,and reduce oxygen consumption and the production of extracellular matrix,thus reshaping the tumor microenvironment and inhibiting tumor metastasis.DOX further stimulates the body’s immune response by inducing immunogenic cell death,and autophagy amplifies this immune response.The synergy of DOX and 3BP can promote the maturation of DCs,increase the accumulation of Ths and CTLs,and effectively inhibit the expression of PD-L1,activate the systemic immune response,demonstrating good therapeutic effects in inhibiting primary tumors and tumor lung metastasis.In conclusion,a pH sensitive and autophagy sensitive nanoplatform was constructed,which can induce cell apoptosis and trigger immunogenic death through cascade amplification of autophagy.At the same time,it can relieve tumor hypoxia,reshape immunosuppressive TME,and enhance the therapeutic effect of chemoimmunotherapy.This study provides enlightenment for autophagy to promote immune effect by reshaping tumor microenvironment.