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.