Distant
metastasis of malignant
tumors is considered to be the main culprit for the failure of current antitumor treatments. Conventional single treatments often exhibit limited efficacy in inhibiting
tumor metastasis. Therefore, there is a growing interest in developing collaborative antitumor strategies based on
photothermal therapy (PTT) and
free-radical-generated
photodynamic therapy (
PDT), especially utilizing
oxygen-independent nanoplatforms, to address this challenge. Such antitumor strategies can enhance the therapeutic outcomes by ensuring the cytotoxicity of
free radicals even in the hypoxic tumor microenvironment, thereby improving the effective suppression of primary
tumors. Additionally, these approaches can stimulate the production of
tumor-associated
antigens and amplify the immunogenic cell death (ICD) effects, potentially feasible for enhancing the therapeutic outcomes of
immunotherapy. Herein, we fabricated a functional nanosystem that co-loads IR780 and 2,2'-azobis[2-(2-imidazolin-2-yl)
propane]-dihydrochloride (AIPH) to realize PTT-triggered thermodynamic combination
therapy via the
oxygen-independent pathway for the elimination of primary
tumors. Furthermore, the nanocomposites were surface-decorated with a predesigned complex
peptide (PLGVRGC-anti-PD-L1 peptide, MMP-sensitive), which facilitated the
immunotherapy targeting distant
tumors. Through the specific recognition of
matrix metalloproteinase (
MMP), the sensitive segment on the obtained aNC@IR780A was cleaved. As a result, the freed anti-PD-L1
peptide effectively blocked immune checkpoints, leading to the infiltration and activation of T cells (CTLs). This nanosystem was proven to be effective at inhibiting both primary
tumors and distant
tumors, providing a promising combination strategy for
tumor PTT/TDT/
immunotherapy.