Photodynamic therapy (PDT) combined with immunotherapy has become a promising antitumor strategy. However, precise regulation of the activation of antitumor immunity and effective reversion of immunosuppressive tumor microenvironment (TME) remains challenging. In this paper, a novel co-delivery nanomedicine is developed to solve these issues for photodynamic amplified immunotherapy. Specifically, the glycolysis inhibitor (Lon) is coupled with PD1/PDL1 blocker (BMS-1) by thioketal linkage to form smartly responsive prodrug LTB , which could further encapsulate photosensitizer chlorine e6 (Ce6) to construct a co-delivery nanoplatform ( LTB-6 NPs ) by self-assembly. Of note, LTB-6 NPs possess favorable stability, uniform morphology and improved cellular uptake. More importantly, LTB-6 NPs are capable of inhibiting glycolysis and blocking PD1/PDL1, which could greatly improve the immunosuppressive TME to promote immune activation. LTB-6 NPs -mediated PDT not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. In vivo experiments indicate that intravenously injected LTB-6 NPs remarkably suppresses the tumor growth while leads to a minimized side effect. This research provides a multi-synergized strategy for developing effective photodynamic nanoplatforms in tumor treatment.
Gongjie Ye,Linglan Tu,Zhuduo Li,Xiangyu Li,Xiaoliang Zheng,Yongfei Song
Synaptopodin 2 (SYNPO2) plays a pivotal role in regulating tumor growth, development and progression in bladder urothelial Carcinoma (BLCA). However, the precise biological functions and mechanisms of SYNPO2 in BLCA remain unclear. Based on TCGA database‑derived BLCA RNA sequencing data, survival analysis and prognosis analysis indicate that elevated SYNPO2 expression was associated with poor survival outcomes. Notably, exogenous SYNPO2 expression significantly promoted tumor invasion and migration by upregulating vimentin expression in BLCA cell lines. Enrichment analysis revealed the involvement of SYNPO2 in humoral immune responses and the PI3K/AKT signaling pathway. Moreover, increased SYNPO2 levels increased the sensitivity of BLCA to PI3K/AKT pathway‑targeted drugs while being resistant to conventional chemotherapy. In in vivo BLCA mouse models, SYNPO2 overexpression increased pulmonary metastasis of 5637 cells. High SYNPO2 expression led to increased infiltration of innate immune cells, particularly mast cells, in both nude mouse model and clinical BLCA samples. Furthermore, tumor immune dysfunction and exclusion score showed that patients with BLCA patients and high SYNPO2 expression exhibited worse clinical outcomes when treated with immune checkpoint inhibitors. Notably, in the IMvigor 210 cohort, SYNPO2 expression was significantly associated with the population of resting mast cells in BLCA tissue following PD1/PDL1 targeted therapy. In conclusion, SYNPO2 may be a promising prognostic factor in BLCA by modulating mast cell infiltration and exacerbating resistance to immune therapy and conventional chemotherapy.
Tumor recurrence and metastasis after surgery remain challenges for tumor treatment. Strategy that can promote the immunogenicity , activate adaptative immune response and eliminate post-operative immunosuppression would be a promising way to achieve a desired clinical benefit. In this study, immunogenic cell death (ICD) priming anti-tumor adaptive immune response was executed to potentiate immune checkpoint blockade (ICB) therapy through the PD1/PDL1 pathway for postsurgical treatment. Here, we present a bio-responsive and cargo-catchable gel depot composed of pullulan and chitosan cross-linking through matrix metalloproteinase (MMP) sensitive peptide for co-delivery of anti-programmed death-ligand 1 antibody (aPDL1) and doxorubicin -encapsulated liposomes (DOX-Lip). This drug carrier showed expected ability to respond to the highly expressed MMP in postsurgical tumor microenvironment (TME). In vivo studies on 4T1 breast tumor mouse model demonstrated that the gel depot could efficiently prolong the mouse survival after tumor resection by preventing tumor recurrence and metastasis. The results suggested that ICD combining with PD1/PDL1 blockade based on the bio-responsive and cargo-catchable gel depot could facilitate the maturation of DCs and reverse the immunosuppressive environment in tumor resection area, thus amplifying the systemic anti-tumor immune response.
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