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Despite significant breakthroughs in immunotherapy, the limitations of inadequate immune stimulation and stubborn immune resistance continue to present opportunities and challenges. Therefore, a two‐pronged approach, encompassing the activation of immunogenic cell death (ICD) and blocking the indoleamine 2,3‐dioxygenase (IDO)‐mediated pathway, is devised to elicit systemic anti‐tumor immunity and alleviate immunosuppression. Herein, a tumor microenvironment (TME)‐specific driven nanoagent is composed of a tetrasulfide bond‐bridged mesoporous silica layer (MON) coated up‐conversion nanoparticles as a nano‐carrier, combines Fe2+, curcumin, and indoximod for operating chemodynamic therapy/chemotherapy/immunotherapy. The consumption of glutathione (GSH) caused by MON degradation, the Fenton reaction of Fe2+, and curcumin triggering mitochondrial damage collectively exacerbate the oxidative stress, leading to a violent immunoreaction and reversal of the immunosuppressive TME through a combination of IDO‐inhibitors. Meanwhile, upconversion luminescence (UCL) imaging serves as a significant guiding tool for drug delivery and the treatment of nanoagents. In vivo and in vitro experiment results demonstrate that the nanosystem not only effectively inhibits the growth of primary tumors but also induces immune priming and memory effects to reject re‐challenged tumors. The strategy as a complementary approach displays great potential for future immunotherapy along with other multimodal treatment modes. [ABSTRACT FROM AUTHOR]

Traditionally referred to as "metabolic junk", lactate has now been recognized as essential "energy currency" and crucial "messenger" that contributes to tumor evolution, immunosuppression, etc., thus presenting a promising strategy for antitumor interventions. Similarly, kynurenine (Kyn) also exerts an immunosuppressive function, thereby significantly compromising the effectiveness of immunotherapy. This study proposes and validates a strategy for enhancing immunotherapy through photothermal‐assisted depletion of lactate sustained by cycle‐like O2 supply, with blocking the tryptophan (Trp)/Kyn metabolic pathway. In brief, a nanozyme therapeutic agent (PNDPL) is constructed, which mainly consists of PtBi nanozymes, lactate oxidase (LOX) and the indoleamine 2,3‐dioxygenase (IDO) inhibitor NLG919. The PtBi nanozymes, which exhibit a catalase (CAT)‐like activity, form a positive feedback loop with LOX to consume lactate while self‐supplying O2. Moreover, PtBi nanozymes retain enzyme‐like performance even in a slightly acidic tumor microenvironment. Under 1064 nm irradiation, photothermal therapy (PTT) not only induces tumor cell death but also accelerates lactate exhaustion. Therefore, the combination of lactate depletion‐induced starvation therapy and PTT, along with the blocking of IDO‐mediated immune escape, effectively inhibits tumor growth and reverses immunosuppressive microenvironment, thus preventing tumor metastasis. This study represents the first investigation into the synergistic antitumor effects by lactate metabolism regulation and IDO‐related immunotherapy. [ABSTRACT FROM AUTHOR]

Chemo‐photodynamic therapy nanodelivery systems provide a potential strategy to enhance anticancer effect. However, the treatment efficiency of stimuli‐responsive nanotheranostics remains a challenge owing to off‐target properties, poor tissue penetration, and slow drugs release. Herein, di‐selenide‐bridged mesoporous silica (Se‐Se‐mSiO2) is introduced into a near‐infrared (NIR) light triggered and tumor microenvironment (TME)‐activated intelligent nanoplatform (UCNPs@mSiO2‐Ce6@Se‐Se‐mSiO2(DOX)@HA (UCSSDH)) realizing burst drug release on demand. Typically, the UCSSDH actively targets cancer cells and accumulates in tumor site through hyaluronic acid (HA). Then, under the irradiation of 980 nm NIR light, the upconverted 650 nm emission light activates photosensitizer Ce6 to produce the singlet oxygen (1O2) for photodynamic therapy (PDT). More importantly, 1O2 further cleaves di‐selenide bonds which are sensitive to reactive oxygen species (ROS), driving the rapid degradation of Se‐Se‐mSiO2 accompanied by the burst release of doxorubicin (DOX). Consequently, UCSSDH achieves efficient chemo‐photodynamic therapy of tumors. Last but not least, the upconversion nanoparticles (UCNPs) perform upconversion luminescence (UCL) imaging to monitor the drugs delivery. Collectively, an intelligent drug delivery system integrating therapeutic, monitoring, and targeting is exploited for NIR light‐triggered synergistic tumor therapy. This study broadens fresh vision into the development of controlled drug release and provides a momentous thought for potential clinical cancer therapy. [ABSTRACT FROM AUTHOR]