Fig. 8. TRPV1 blockade amplifies thermo-immunotherapeutic efficacy and immune response against subcutaneous PANC02 pancreatic tumors using IS-Micelles/aPD-L1 combination.

a Timeline for the treatment of subcutaneous PANC02 tumor model. Tumor growth profiles (b) and survival curves (c) of the mice bearing large PANC02 tumor model (250–300 mm³) treated with various formulations (n = 7 mice per group). Quantification of CD45⁺CD11b⁺Gr−1⁺ MDSCs (d), CD11b⁺F4/80⁺CD206⁺ TAMs (e) and CD11b⁺F4/80⁺CD80⁺ TAMs (f) inside PANC02 tumors at 72 h post-treatment with various formulations (n = 5 mice per group). g Ratio of CD11b⁺F4/80⁺CD80⁺ TAMs to CD11b⁺F4/80⁺CD206⁺ TAMs inside large PANC02 tumors at 72 h post-treatment with various formulations (n = 5 mice per group). h Quantification of matured dendritic cells (CD11c⁺CD80⁺CD86⁺ DCs) inside tumor-draining lymph nodes at 72 h post-treatment with various formulations (n = 5 mice per group). Quantification of tumor-infiltrating CD45⁺CD3⁺CD8⁺ CTLs (i) and CD45⁺CD3^-CD335⁺ NK cells (j) in PANC02 tumors at 72 h post-treatment with various formulations (n = 5 mice per group). k Schematic illustration of ECM remodeling to facilitate aPD-L1 infiltration for inducing durable immune response via TRPV1 blockade-synergized thermotherapy. Upon TRPV1 blockade, nuclear translocation of HSF1 is effectively blocked which subsequently suppresses TGFβ1 upregulation and secretion, thus leading to inhibition of CAFs proliferation and activation-mediated ECM proteins deposition, ultimately promoting the infiltration of aPD-L1 and immune cells (e.g. NK cells and T lymphocytes) for durable immune response. Dash lines indicate the failure of downstream signals transduction upon blockade of hyperthermia-activated TRPV1 channel. The mice in b–j were treated with PBS (G1), aPD-L1 (G2), Abraxane/GEM (G3), I-Micelles under light irradiation (+) (G4), I-Micelles/aPD-L1 under light irradiation (+) (G5), IS-Micelles (G6), IS-Micelles/aPD-L1 (G7), IS-Micelles under light irradiation (+) (G8), and IS-Micelles/aPD-L1 under light irradiation (+) (G9), respectively. Data are presented as mean ± SD (b, d–j). For b and d–j, statistical significance was determined by one-way ANOVA with Tukey’s post hoc test. For c, statistical significance was calculated by log-rank test. Source data are provided as a Source Data file.