In this study, an organic semiconducting pro‐nanostimulant (OSPS) with a near‐infrared (NIR) photoactivatable immunotherapeutic action for synergetic cancer therapy is presented. OSPS comprises a semiconducting polymer nanoparticle (SPN) core and an immunostimulant conjugated through a singlet oxygen (1O2) cleavable linkers. Upon NIR laser irradiation, OSPS generates both heat and 1O2 to exert combinational phototherapy not only to ablate tumors but also to produce tumor‐associated antigens. More importantly, NIR irradiation triggers the cleavage of 1O2‐cleavable linkers, triggering the remote release of the immunostimulants from OSPS to modulate the immunosuppressive tumor microenvironment. Thus, the released tumor‐associated antigens in conjunction with activated immunostimulants induce a synergistic antitumor immune response after OSPS‐mediated phototherapy, resulting in the inhibited growth of both primary/distant tumors and lung metastasis in a mouse xenograft model, which is not observed for sole phototherapy.

Photodynamic therapy( PDT) holds great promise for cancer therapy; however,its efficacy is often compromised by tumor hypoxia. Herein, we report the synthesis of as emiconducting polymer nanoprodrug (SPNpd) that not only efficiently generates singlet oxygen ( 1 O 2 )u nder NIR photoirradiation but also specifically activates its chemotherapeutic action in hypoxic tumor microenvironment. SPNpd is selfassembled from aa mphiphilic polymer brush, which comprises alight-responsive photodynamic backbone grafted with poly(ethylene glycol) and conjugated with ac hemodrug through hypoxia-cleavable linkers.T he well-defined and compact nanostructure of SPNpd (30 nm) enables accumulation in the tumor of living mice.O wing to these features, SPNpd exerts synergistic photodynamic and chemo-therapy, and effectively inhibits tumor growth in ax enograft tumor mouse model. This study represents the first hypoxia-activatable phototherapeutic polymeric prodrug system with ah igh potential for cancer therapy.

Immunometabolic intervention has been applied to treat cancer via inhibition of certain enzymes associated with intratumoral metabolism. However, small-molecule inhibitors and genetic modification often suffer from insufficiency and off-target side effects. Proteolysis targeting chimeras (PROTACs) provide an alternative way to modulate protein homeostasis for cancer therapy; however, the always-on bioactivity of existing PROTACs potentially leads to uncontrollable protein degradation at non-target sites, limiting their in vivo therapeutic efficacy. We herein report a semiconducting polymer nano-PROTAC (SPNpro) with phototherapeutic and activatable protein degradation abilities for photo-immunometabolic cancer therapy. SPNpro can remotely generate singlet oxygen (1O2) under NIR photoirradiation to eradicate tumor cells and induce immunogenic cell death (ICD) to enhance tumor immunogenicity. Moreover, the PROTAC function of SPNpro is specifically activated by a cancer biomarker (cathepsin B) to trigger targeted proteolysis of immunosuppressive indoleamine 2,3-dioxygenase (IDO) in the tumor of living mice. The persistent IDO degradation blocks tryptophan (Trp)-catabolism program and promotes the activation of effector T cells. Such a SPNpro-mediated in-situ immunometabolic intervention synergizes immunogenic phototherapy to boost the antitumor T-cell immunity, effectively inhibiting tumor growth and metastasis. Thus, this study provides a polymer platform to advance PROTAC in cancer therapy.

In particular, activatable immunotherapeutic nanoplatforms have received tremendous attention as these nanomedicines can exert immunotherapeutic action only in response to certain stimuli, which largely promoted the specificity and controllability of immunotherapeutic response at designated sites. [7] On account of the restricted immune cell infiltration and dysfunction of immune cells by metabolic stress, [8] modulation of cancer metabolic pathways with immunotherapeutic drugs to reprogramme the tumor immune microenvironment has emerged as a promising approach, namely, immunometabolic cancer therapy. [9] Modulation of lactic acid production, [10] inhibition of glutamine catabolism, [11] and suppression of tryptophan catabolism [12] represent some attractive targets for immunometabolic intervention and tumor suppression. Till now, several small-molecule inhibitors have been developed for immunometabolic intervention and entered clinical testing, such as navoximod (also known as NLG919), HTI-1090 (also known as SHR9146), and DN1406131. [13] However, small-molecule inhibitors are commonly unable to maintain sustainable immune response and suffer from drug resistance and some adverse side effects, which hinders their therapeutic efficacy in the modulation of immunometabolism. [14] In contrast to small-molecule inhibitors, enzyme immunotherapeutics possess highly selective capabilities in catalyzing shifts in the local availability of immunostimulatory and immunosuppressive signals. [15] Additionally, enzyme treatment eliminates immunosuppressive metabolite irrespective of different pathways and alleviates concerns of mutation and the drug resistance, thus overpassing many limitations of small-molecule inhibitors. [16] However, the clinical success of enzyme immunotherapeutics frequently hinges upon achieving sustained biocatalysis over relevant time scales at the designated site owing to rapid clearance enzyme degradation via proteases and insufficient accumulation at target tissues. [17] Therefore, the integration of enzyme immunotherapeutics with activable nanoplatforms could be a promising strategy to address these issues. Among a variety of stimuli for remote control, light has served as a paradigm for noninvasiveness, high spatial-temporal controllability, and low toxicity. [18] Particularly, near-infrared

Regulation of transgene systems is needed to develop innovative medicines. However, noninvasive remote control of gene expression has been rarely developed and remains challenging. We herein synthesize a near-infrared (NIR) absorbing dendronized semiconducting polymer (DSP) and utilize it as a photothermal nanocarrier not only to efficiently deliver genes but also to spatiotemporally control gene expression in conjunction with heat-inducible promoter. DSP has a high photothermal conversion efficiency (44.2 %) at 808 nm, permitting fast transduction of NIR light into thermal signals for intracellular activation of transcription. Such a DSP-mediated remote activation can rapidly and safely result in 25- and 4.5-fold increases in the expression levels of proteins in living cells and mice, respectively. This study thus provides a promising approach to optically regulate transgene systems for on-demand therapeutic transgene dosing.