Construction and synergistic effect of a CGT-Cls-PTX/CM nanocodelivery system targeting the tumor microenvironment

Immunosuppression within the tumor microenvironment (TME) is a major factor driving pancreatic cancer progression and therapeutic resistance. To address this challenge, we developed a nano-codelivery system, CGT (Cilengitide)-Cls-PTX (paclitaxel)/CM (cell membrane), for the co-delivery of PTX and tumor cell lysate-derived antigens from pancreatic cancer cells (from human pancreatic cancer PANC-1 and mouse pancreatic cancer PANC02 cells). The system was constructed by synthesizing an integrin<i>α</i>v<i>β</i>3-targeting lipid, DSPE-PEG₂₀₀₀-CGT, and fusing PTX-loaded liposomes with pancreatic cancer cell membranes. This strategy enables preferential accumulation in the TME, where tumor antigens are released to stimulate dendritic cell (DC) maturation and relieve TME immunosuppression, thereby achieving synergistic antitumor efficacy via PTX-mediated tumor cell killing and antigen-induced immune activation. Physicochemical characterization by¹H-nuclear magnetic resonance, transmission electron microscopy, and Western blot confirmed successful synthesis and membrane fusion. Immunostimulatory activity was evaluated using ELISA, flow cytometry, and co-culture assays, and therapeutic efficacy was assessed in a PANC02 murine pancreatic cancer model with Cls-PTX as the control. CGT-Cls-PTX/CM significantly enhanced DC maturation, upregulated co-stimulatory molecules (CD80, CD86), and promoted secretion of interleukin-6 (IL-6) and interleukin-12 (IL-12). Furthermore, it increased CD4⁺and CD8⁺T-cell proliferation, elevated interferon-<i>γ</i>(IFN-<i>γ</i>) production, suppressed transforming growth factor-<i>β</i>, and facilitated cytotoxic T lymphocyte infiltration into tumor tissues. Overall, CGT-Cls-PTX/CM effectively remodels the immunosuppressive TME, achieving synergistic antitumor effects through combined chemotherapy and immune modulation. This strategy offers a promising approach for enhancing immunotherapeutic efficacy against pancreatic ductal adenocarcinoma, a prototypical 'cold' tumor resistant to immune checkpoint therapy.