Cancer immunotherapy has shown tremendous potential to train the intrinsic immune system against malignancy in the clinic. However, the extracellular matrix (ECM) in tumor microenvironment is a formidable barrier that not only restricts the penetration of therapeutic drugs but also prevents the infiltration of antitumor immune cells. We herein report a semiconducting polymer-based ECM nanoremodeler (SPNcb) to combine photodynamic antitumor activity with cancer-specific inhibition of collagen-crosslinking enzymes (lysyl oxidase (LOX) family) for activatable cancer photo-immunotherapy. SPNcb is self-assembled from an amphiphilic semiconducting polymer conjugated with a LOX inhibitor (β-aminopropionitrile, BAPN) via a cancer biomarker (cathepsin B, CatB)cleavable segment. BAPN can be exclusively activated to inhibit LOX activity in the presence of the tumoroverexpressed CatB, thus blocking collagen crosslinking and decreasing ECM stiffness. Such an ECM nanoremodeler synergizes immunogenic phototherapy and checkpoint blockade immunotherapy to improve the tumor infiltration of cytotoxic T cells, inhibiting tumor growth and metastasis.
Phototherapy including photodynamic therapy and photothermal therapy provides an alternative pathway for cancer therapy. However, single-mode phototherapy suffers from low therapeutic efficiency; therefore, other therapeutic modalities are often combined to enhance the antitumor effect. In this review, we summarize the recent progress of semiconducting polymer nanoparticle (SPN) based activatable nanomedicines for combinational cancer therapy. With ideal optical properties, SPNs function not only as drug carriers but also as phototherapeutic agents (photodynamic or photothermal). Under the internal (such as acidic pH, ROS, and hypoxia) or external stimuli (such as light), SPN-based activatable nanomedicines can be specifically activated to release therapeutic agents at tumor sites, which reduces off-target probabilities and thus enhances the biosafety of the nanomedicine.
Checkpoint immunotherapy holds great potential to treat malignancies via blocking the immunosuppressive signaling pathways, which however suffers from inefficiency and off‐target adverse effects. Herein, checkpoint nano‐proteolysis targeting chimeras (nano‐PROTACs) in combination with photodynamic tumor regression and immunosuppressive protein degradation to block checkpoint signaling pathways for activatable cancer photo‐immunotherapy are reported. These nano‐PROTACs are composed of a photosensitizer (protoporphyrin IX, PpIX) and an Src homology 2 domain‐containing phosphatase 2 (SHP2)‐targeting PROTAC peptide (aPRO) via a caspase 3‐cleavable segment. aPRO is activated by the increased expression of caspase 3 in tumor cells after phototherapeutic treatment and induces targeted degradation of SHP2 via the ubiquitin‐proteasome system. The persistent depletion of SHP2 blocks the immunosuppressive checkpoint signaling pathways (CD47/SIRPα and PD‐1/PD‐L1), thus reinvigorating antitumor macrophages and T cells. Such a checkpoint PROTAC strategy synergizes immunogenic phototherapy to boost antitumor immune response. Thus, this study represents a generalized PROTAC platform to modulate immune‐related signaling pathways for improved anticancer therapy.
Photothermal immunotherapy is a combinational cancer therapy modality, wherein the photothermal process can noninvasively ablate cancer and efficiently trigger cancer immunogenic cell death to ignite antitumor immunity. However, cancer cells can resist the cytotoxic lymphocyte-mediated antitumor effect via expressing serine protease inhibitory proteins (serpins) to deactivate proteolytic immunoproteases. Herein, we report a smart polymer nanoagonist (SPND) with second near-infrared (NIR-II) phototherapeutic ablation and tumor-specific immunoprotease granzyme B (GrB) restimulation for cancer photothermal immunotherapy. SPND has a semiconducting polymer backbone grafted with a small-molecule inhibitor of serpinB9 (Sb9i) via a glutathione (GSH)-cleavable linker. Once in the tumor, Sb9i can be specifically liberated from SPND to inhibit serpinB9, restimulating the activity of GrB to enhance cancer immunotherapy. Moreover, SPND induces photothermal therapy for direct tumor ablation and immunogenic cancer cell death (ICD) under NIR-II photoirradiation. Therefore, such a smart nanoagonist represents a way toward combination photothermal immunotherapy (PTI).
Real-time imaging of immune systems benefits early diagnosis of disease and precision immunotherapy; however, most existing imaging probes either have "always-on" signals with poor correlation to immune responses, or rely on light excitation with limited imaging depth. In this work, an ultrasound-induced afterglow (sonoafterglow) nanoprobe is developed to specifically detect granzyme B for accurate imaging of T-cell immunoactivation in vivo. The sonoafterglow nanoprobe (Q-SNAP) consists of sonosensitizers, afterglow substrates, and quenchers. Upon ultrasound irradiation, sonosensitizers generate singlet oxygen, which converts substrates to high-energy dioxetane intermediates that slowly release energy after ultrasound cessation. Due to the proximity, energy from substrates can be transferred to quenchers, leading to afterglow quenching. Only in the presence of granzyme B, quenchers are liberated from Q-SNAP, resulting in bright afterglow emission with a limit of detection (LOD, 2.1 nm) much lower than most existing fluorescent probes. Due to the deep-tissue-penetrating ultrasound, sonoafterglow can be induced through a tissue of 4 cm thickness. Based on the correlation between sonoafterglow and granzyme B, Q-SNAP not only distinguishes autoimmune hepatitis from healthy liver as early as 4 h after probe injection, but also effectively monitors the cyclosporin-A-mediated reversal of T-cell hyperactivation. Q-SNAP thus offers the possibilities of dynamic monitoring of T-cell dysfunction and evaluation of prophylactic immunotherapy in deep-seated lesions.
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