Thi My Hue Huynh

Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell–cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG-b-C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm2), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.

Infiltration of cytotoxic T lymphocytes into hypovascular metastases offers significant potential for suppressing even the most intractable metastatic tumors, with dendritic cells (DCs) serving as pivotal initiators of antitumor immune responses during immunotherapy. However, the immune-privileged nature of hypovascular lung metastases combined with the inherently low immunogenicity of tumor clusters poses substantial barriers to effective lymphocyte recruitment. Here, a pH-responsive lung metastatic-targeted catalyst containing the tumor penetration polymer (TP)/solid lipids (SL)-coated Prussian blue (TP-SL@PB)-enhanced PD-L1 siRNA delivery and self-cascade antigen capture is developed for reprogramming immunodeficiency. Intravenously injected TP-SL@PB accumulated in the blood vessel-poor lung metastases via the organ-selective targeting and charge conversion of TP. In tumor clusters, SL@PB exerts catalytic and lysosomal escape effects, easily enhancing siRNA delivery and thus downregulating PD-L1. Catalysis also promotes the release of tumor-associated antigens (TAAs), including neoantigens and damage-associated molecular patterns. Subsequently, both positive TPs and SLs on PBs can act as antigen sponges to deliver TAAs to dendritic cells, thereby inducing long-term immune activation. TP-SL@PB acts as a hypovascularized lung metastasis-penetrating catalytic nanosponge, selecting T cells to infiltrate metastases and enhance immunotherapy.

Abstract T lymphocytes play a central role in immunotherapy, utilizing physical interactions to actively inhibit the development of metastases. However, tumor immune privilege and heterogeneity pose challenges by protecting against immune attacks and limiting immune cell infiltration into tumors, particularly in invasive metastatic clusters. Here, a tumor penetrating magnetic particles (TUP) containing the cascade‐responsive cell membrane‐mimetic copolymer (zwitterionic 2‐methacryloyloxyethyl phosphorylcholine‐co‐3‐hydroxypyridin‐4‐one, PH) and cuproptosis molecules (elesclomol‐copper, EsCu) for programming T cell infiltration is developed. The intravenously injected TUP accumulates at the tumor via the charge conversion of PH and hyperthermia effects of TUP. In metastatic clusters, ES and Cu, triggered by intracellular environments and hyperthermia, are readily released. ES and Cu simultaneously induce cuproptosis of cancer cells and stimulate immune responses. This process destroys self‐defense mechanisms and exacerbates cytotoxicity. The therapies facilitate the release of tumor‐associated antigens, including neoantigens and damage‐associated molecular patterns. Following this, the 3‐hydroxypyridin‐4‐one groups on TUP act as antigen reservoirs, transporting autologous tumor‐associated antigens to dendritic cells, thereby inducing prolonged immune activation. TUP acts as an antigen reservoir in copper apoptosis‐mediated lung metastasis, promoting the accumulation of immune cells in metastatic clusters and effectively preventing the progression of metastatic tumors.

Abstract The recruitment of T lymphocytes holds great potential for suppressing the most aggressive glioblastoma (GBM) recurrence with immunotherapy. However, the phenomenon of immune privilege and the generally low immunogenicity of vaccines often reduce the presence of lymphocytes within brain tumors, especially in brain tumor recurrence clusters. In this study, an implantable self‐cascading catalytic therapy and antigen capture scaffold (CAS) that can boost catalytic therapy efficiency at post‐surgery brain tumor and capture the antigens via urethane‐polyethylene glycol‐polypropylene glycol (PU‐EO‐PO) segments are developed for postoperative brain immunotherapy. The CAS consists of 3D‐printed elastomers modified with iron (Fe 2+ ) metal‐organic frameworks (MOFs, MIL88) and acts as a programmed peroxide mimic in cancer cells to initiate the Fenton reaction and sustain ROS production. With the assistance of chloroquine (CQ), autophagy is inhibited through lysosome deacidification, which interrupts the self‐defense mechanism, further enhances cytotoxicity, and releases antigens. Then, CAS containing PU‐EO‐PO groups acts as an antigen depot to detain autologous tumor‐associated antigens to dendritic cells maturation and T cell augments for sustained immune stimulation. CAS enhanced the immune response to postoperative brain tumors and improved survival through brain immunotherapy.