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Eosinophils are important immune effector cells that affect T cell‐mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil‐activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T‐cell immunity for activated cancer photo‐immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1O2‐cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1O2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe‐mediated photo‐immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and T cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The efficacy of combination immunotherapy has been limited by tumor specificity and immune‐related adverse events (irAEs). Herein, we report the development of polymeric STING pro‐agonists (PSPA), whose sono‐immunotherapeutic efficacy is activated by sono‐irradiation and elevated glutathione (GSH) within the tumor microenvironment (TME). PSPA is composed of sonosensitizers (semiconducting polymer) and STING agonists (MSA‐2) via the GSH‐activatable linkers. Under sono‐irradiation, PSPA serves as a sonosensitizer to generate 1O2 and induce immunogenic cell death (ICD) of malignant tumor cells. Furthermore, MSA‐2 is released specifically in tumor microenvironment with highly expressed GSH, minimizing off‐target side effects. The activation of the STING pathway elevates the interferon‐β level and synergizes with SDT to enhance the anti‐tumor response. Therefore, this work proposes a universal approach for spatiotemporal regulation of cancer sono‐immunotherapy. [ABSTRACT FROM AUTHOR]

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 tumor‐overexpressed 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. [ABSTRACT FROM AUTHOR]

Protease inhibitors can modulate intratumoral metabolic processes to reprogram the immunosuppressive tumor microenvironment (TME), which however suffer from the limited efficacy and off‐targeted side effects. We report smart nano‐proteolysis targeting chimeras (nano‐PROTACs) with phototherapeutic ablation and cancer‐specific protein degradation to reprogram the TME for photo‐metabolic cancer immunotherapy. This nano‐PROTAC has a semiconducting polymer backbone linked with a cyclooxygenase 1/2 (COX‐1/2)‐targeting PROTAC peptide (CPP) via a cathepsin B (CatB)‐cleavable segment. CPP can be activated by the tumor‐overexpressed CatB to induce the degradation of COX‐1/2 via the ubiquitin‐proteasome system. The persistent degradation of COX‐1/2 depletes their metabolite prostaglandin E2 which is responsible for activation of immune suppressor cells. Such a smart PROTAC strategy synergized with phototherapy specifically reprograms the immunosuppressive TME and reinvigorates antitumor immunity. [ABSTRACT FROM AUTHOR]