Nanomaterial-based tumor photothermal therapy (PTT) has attracted increasing attention and been a promising method for cancer treatment because of its low level of adverse effects and noninvasiveness. However, thermotherapy alone still cannot control tumor metastasis and recurrence. Here, we developed surface-functionalized modified copper sulfide nanoparticles (CuS NPs). CuS NPs can not only be used as photothermal mediators for tumor hyperthermia but can adsorb tumor antigens released during hyperthermia as an antigen-capturing agent to induce antitumor immune response. We selected maleimide polyethylene glycol-modified CuS NPs (CuS NPs-PEG-Mal) with stronger antigen adsorption capacity, in combination with an immune checkpoint blocker (anti-PD-L1) to evaluate the effect of hyperthermia, improving immunotherapy in a 4T1 breast cancer tumor model. The results showed that hyperthermia based on CuS NPs-PEG-Mal distinctly increased the levels of inflammatory cytokines in the serum, leading to a tumor immunogenic microenvironment. In cooperation with anti-PD-L1, PTT mediated by CuS NPs-PEG-Mal enhanced the number of tumor-infiltrating CD8 + T cells and inhibited the growth in primary and distant tumor sites of the 4T1 tumor model. The therapeutic strategies provide a simple and effective treatment option for metastatic and recurrent tumors.

Immunotherapy holds great promise for cancer treatment. The key to improving the therapeutic effect is to drive the patient's own immune system to produce a strong, effective, and enduring tumor-specific immune response. Engineered nanoplatforms show promising potential in strengthening antitumor immune responses. However, current nanotherapeutic platforms based on exogenous responses stimulate the immune system only in a transitory and limited manner, which translates into insufficient immune activation and a low therapeutic efficacy. A novel targeted nano-immunostimulant (ZGS-Si-Pc@HA) is fabricated by coupling persistent luminescence nanoparticles with a photosensitizer and hyaluronic acid for sustained immune stimulation upon irradiation with biological window (659 nm) light. ZGS-Si-Pc@HA persistently drives reactive oxygen species production to induce immunogenic cell death, causing a durable tumor-specific immune response. Upon intratumoral injection, ZGS-Si-Pc@HA effectively alleviates immune tolerance and promotes T lymphocyte tumor infiltration. Further, ZGS-Si-Pc@HA enhances the therapeutic effect of checkpoint blockade immunotherapy, effectively inhibiting bilateral tumor growth and triggering an immunological memory effect. Nano-immunostimulants not only provide a new way to boost cancer immunotherapy, but also offer a reliable strategy for fighting cancer metastasis and recurrence clinically.