Activating antigen-specific T cells by the dual action of paclitaxel to enhance tumor immunotherapy

Immunotherapy often encounters obstacles due to the prevalence of the cold tumor phenotype. Although the combination of immunogenic cell death (ICD) inducers and adjuvants has been shown to elicit remarkable immune responses, the use of multiple therapeutic agents presents inherent difficulties in constructing a delivery platform with optimal performance. Inspired by the dual function of paclitaxel (PTX) as an ICD inducer and Toll-like receptor 4 (TLR4) agonist, a "two birds with one stone" strategy is developed to address these challenges in anti-tumor immunotherapy. Briefly, the photosensitizer indocyanine green (ICG) and paclitaxel-loaded cationic albumin nanoparticles (PTX-cNPs) are co-loaded in a photocrosslinked hyaluronic acid and Pluronic F127-derived gel platform (ICG+PTX-cNPs gel) to afford a "plum-pudding" gel implant system. On the one hand, PTX-cNPs and photothermal therapy (PTT) synergistically induce ICD to enhance tumor immunogenicity. On the other hand, PTX-cNPs not only act as TLR4 agonist but also capture antigens to promote dendritic cell maturation and activate antigen-specific T cells. Overall, the implementation of the "two birds with one stone" strategy activates the systemic immune response and effectively inhibits tumor growth. This strategy provides a viable regimen for the management of appropriate doses to afford PTX as potent TLR4a.