Postoperative recurrence and metastasis are still the main challenges of cancer therapy.Tumor vaccines that induce potent and long-lasting immune activation have great potential for postoperative cancer therapy.Howeve...Postoperative recurrence and metastasis are still the main challenges of cancer therapy.Tumor vaccines that induce potent and long-lasting immune activation have great potential for postoperative cancer therapy.However,the clinical effects of therapeutic tumor vaccines are unsatisfactory due to immune escape caused by the lack of immunogenicity after surgery and the local fibrosis barrier of the tumor which limits effector T cell infiltration.To overcome these challenges,we developed an injectable hydrogelbased tumor vaccine,RATG,which contains whole tumor cell lysates(TCL),Toll-like receptor(TLR)7/8 agonist imiquimod(R837)and an antifibrotic drug ARV-825.TCL and R837 were loaded onto the hydrogel to achieve a powerful reservoir of antigens and adjuvants that induced potent and lasting immune activation.More importantly,ARV-825 could be slowly and sustainably released in the tumor resection cavity to downregulateα-smooth muscle actin(α-SMA)and collagen levels,disintegrate fibrosis barriers and promote T cell infiltration after immune activation to reduce immune escape.In addition,ARV-825 also directly acted on the remaining tumor cells to degrade bromodomain-containing protein 4(BRD4)which is a critical epigenetic reader overexpressed in tumor cells,inhibiting tumor cell migration and invasion.Therefore,our injectable hydrogel created a powerful immune niche in postoperative tumor resection cavity,significantly enhancing the efficacy of tumor vaccines.Our strategy potently activates the immune system and disintegrates the fibrotic barrier of residual tumors with immune microenvironment remodeling in situ,showing anti-recurrence and anti-metastatic effects,and provides a new paradigm for postoperative treatment of tumors.展开更多
TheαPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes se...TheαPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes secreted in the environment,causing tumor immune evasion.Here,we proposed an exosome biogenesis inhibition strategy to suppress tumor exosomes secretion from the source,reducing the inhibitory effect on T cells and enhancing chemo-immunotherapy efficacy.We developed sulfafurazole homodimers(SAS)with disulfide linkages,effectively releasing the drug in response to glutathione(GSH)and inhibiting 4T1 tumor-derived exosomes secretion.Subsequently,gemcitabine(Gem)was encapsulated to induce immunogenic cell death(ICD).Consequently,Gem@SAS inhibited the secretion of tumor exosomes by more than 70%,increased proliferation and granzyme B secretion ability of T cells by more than 2 times,and showed superior efficacy in breast cancer treatment as well as lung metastasis of breast cancer.展开更多
基金supported by the National Natural Science Foundation of China(No.82102202)Key Research and Development Program Social Development Project of Jiangsu Province(No.BE2023845)Natural Science Foundation of Jiangsu Province(No.BK20210424).
文摘Postoperative recurrence and metastasis are still the main challenges of cancer therapy.Tumor vaccines that induce potent and long-lasting immune activation have great potential for postoperative cancer therapy.However,the clinical effects of therapeutic tumor vaccines are unsatisfactory due to immune escape caused by the lack of immunogenicity after surgery and the local fibrosis barrier of the tumor which limits effector T cell infiltration.To overcome these challenges,we developed an injectable hydrogelbased tumor vaccine,RATG,which contains whole tumor cell lysates(TCL),Toll-like receptor(TLR)7/8 agonist imiquimod(R837)and an antifibrotic drug ARV-825.TCL and R837 were loaded onto the hydrogel to achieve a powerful reservoir of antigens and adjuvants that induced potent and lasting immune activation.More importantly,ARV-825 could be slowly and sustainably released in the tumor resection cavity to downregulateα-smooth muscle actin(α-SMA)and collagen levels,disintegrate fibrosis barriers and promote T cell infiltration after immune activation to reduce immune escape.In addition,ARV-825 also directly acted on the remaining tumor cells to degrade bromodomain-containing protein 4(BRD4)which is a critical epigenetic reader overexpressed in tumor cells,inhibiting tumor cell migration and invasion.Therefore,our injectable hydrogel created a powerful immune niche in postoperative tumor resection cavity,significantly enhancing the efficacy of tumor vaccines.Our strategy potently activates the immune system and disintegrates the fibrotic barrier of residual tumors with immune microenvironment remodeling in situ,showing anti-recurrence and anti-metastatic effects,and provides a new paradigm for postoperative treatment of tumors.
基金supported by the National Natural Science Foundation of China(82473866 and 32471394)Key Research and Development Program Social Development Project of Jiangsu Province(BE2023845,China)Natural Science Foundation of Jiangsu Province(BK20210424,China).
文摘TheαPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes secreted in the environment,causing tumor immune evasion.Here,we proposed an exosome biogenesis inhibition strategy to suppress tumor exosomes secretion from the source,reducing the inhibitory effect on T cells and enhancing chemo-immunotherapy efficacy.We developed sulfafurazole homodimers(SAS)with disulfide linkages,effectively releasing the drug in response to glutathione(GSH)and inhibiting 4T1 tumor-derived exosomes secretion.Subsequently,gemcitabine(Gem)was encapsulated to induce immunogenic cell death(ICD).Consequently,Gem@SAS inhibited the secretion of tumor exosomes by more than 70%,increased proliferation and granzyme B secretion ability of T cells by more than 2 times,and showed superior efficacy in breast cancer treatment as well as lung metastasis of breast cancer.
