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Background Although programmed cell death protein 1 (PD-1)/ programmed cell death-ligand protein 1 (PD-L1) checkpoint blockade immunotherapy demonstrates great promise in cancer treatment, poor infiltration of T cells resulted from tumor immunosuppressive microenvironment (TIME) and insufficient accumulation of anti-PD-L1 (αPD-L1) in tumor sites diminish the immune response. Herein, we reported a drug-loaded microbubble delivery system to overcome these obstacles and enhance PD-L1 blockade immunotherapy. Methods Docetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. The targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models. Results The dying tumor cells induced by DTX release tumor-associated antigens (TAAs), together with R837, promoted the activation, proliferation and recruitment of T cells. Besides, UTMD technology and DTX enhanced the accumulation of αPD-L1 in tumor sites. Moreover, RD@MBs remolded TIME, including the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduction of myeloid-derived suppressor cells (MDSCs). The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases. Conclusion PD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.

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Background Immune checkpoint blockade (ICB) therapies have reshaped tumor treatment by activating the antitumor immune response. However, the antitumor effect of ICB is seriously restricted by the immunosuppressive tumor microenvironment (ITM). A variety of strategies to alleviate the ITM have been investigated. Direct regulation of lactate metabolism in tumor microenvironment holds promise for ITM modulation. Results Glutathione (GSH) -responsive hollow mesoporous organosilicon (HMOP) was successfully fabricated, with monocarboxylate transporter 1/4 inhibitor (diclofenac, DC) and lactate oxidase (LOD) were loaded in/onto the HMOP (designed as DC-HMOP-LOD). DC-HMOP-LOD could spontaneously be biodegraded in tumor microenvironment due to disulfide bonds, and then DC/LOD could be released to exhaust intra/extracellular lactate. Consequently, lactate depletion induced an immunocompetent tumor microenvironment by activating immune-promoting cells including dendritic cells, CD4+ T cells, CD8+ T cells, and natural killer cells, and inactivating immunosuppressive cells containing tumor-associated macrophages and myeloid-derived suppressor cells, ultimately strengthening the antitumor effect of ICB therapy. Conclusion DC-HMOP-LOD effectively hindered the transmission of lactate and directly oxidized lactate, collaboratively depleting lactate in the TME. The synergetic depletion reversed the ITM and could improve the antitumor effects of aPD1-based immunotherapy.

Background Compared with the conventional tumor therapeutic modalities, immune checkpoint blockade (e.g., PD-1/PD-L1) immunotherapy demonstrates great promise in the treatment of metastatic cancers. Although PD-L1 blockade immunotherapy is applied to a variety of tumor types, only a small number of patients respond to this treatment. The efficacy of PD-L1 blockade immunotherapy is based on the expression of PD-L1 on tumor cells and the infiltration of T cells in tumor tissue. Herein, we reported a drug-loaded microbubble delivery system to enhance PD-L1 blockade immunotherapy. Methods Docetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. the targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models. Results The dying tumor cells induced by DTX release TAAs, together with R837, promote the activation, proliferation and recruitment of T cells. Besides, DTX upregulates the expression of PD-L1 on tumor cells, induces the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduces the proportion of myeloid-derived suppressor cells (MDSCs). Also, R837 exhibits satisfactory copolarization effects on TAMs, which synergizes with DTX to alleviate immunosuppression. The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases. Conclusion PD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.