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Low immunogenicity of tumors poses a challenge in the development of effective tumor immunotherapy. However, emerging evidence suggests that certain therapeutic approaches, such as chemotherapy, radiotherapy, and phototherapy, can induce varying degrees of immunogenic cell death (ICD). This ICD phenomenon leads to the release of tumor antigens and the maturation of dendritic cells (DCs), thereby enhancing tumor immunogenicity and promoting immune responses. However, the use of a single conventional ICD inducer often fails to achieve in situ tumor ablation and establish long-term anti-tumor immune responses. Furthermore, the induction of ICD induction varies among different approaches, and the distribution of the therapeutic agent within the body influences the level of ICD and the occurrence of toxic side effects. To address these challenges and further boost tumor immunity, researchers have explored nanosystems as inducers of ICD in combination with tumor immunotherapy. This review examines the mechanisms of ICD and different induction methods, with a specific focus on the relationship between ICD and tumor immunity. The aim is to explore the research advancements utilizing various nanomaterials to enhance the body's anti-tumor effects by inducing ICD. This paper aims to contribute to the development and clinical application of nanomaterial-based ICD inducers in the field of cancer immunotherapy by providing important theoretical guidance and practical references., Competing Interests: The authors declare no conflicts of interests in this work., (© 2024 Peng et al.)

Immune checkpoint blockade (ICB) has shown significant clinical success, yet its responses can vary due to immunosuppressive tumor microenvironments. To enhance antitumor immunity, combining ICB therapy with tumor metabolism reprogramming may be a promising strategy. In this study, we developed a photodynamic immunostimulant called BVC aiming to boost immune recognition and prevent immune escape for metastatic tumor eradication by reprogramming glutamine metabolism. BVC, a carrier free self-assembled nanoparticle, comprises a photosensitizer (chlorin e6), an ASCT2 inhibitor (V9302) and a PD1/PDL1 blocker (BMS-1), offering favorable stability and enhanced drug delivery efficiency. The potent photodynamic therapy (PDT) capability of BVC is attributed to its regulation of glutamine metabolism, which influences the redox microenvironment within tumor tissues. By targeting ASCT2-mediated glutamine metabolism, BVC inhibits glutamine transport and GSH synthesis, leading to the upregulation of Fas and PDL1. Additionally, BVC-mediated PDT induces immunogenic cell death, triggering a cascade of immune responses. Consequently, BVC not only enhances immune recognition between CD8+ T cells and Fas-overexpressing tumor cells but also reduces tumor cell immune escape through PD1/PDL1 blockade, significantly benefiting metastatic tumor eradication. This study paves a novel approach for multi-synergistic tumor treatment. Photodynamic immunostimulant (BVC) is developed through the self-assembly of photosensitizer (Ce6), ASCT2 inhibitor (V9302) and PD1/PDL1 blocker (BMS). Tumor metabolism reprogramming capacity of BVC can inhibit alanine-serine-cysteine transporter 2 (ASCT2) to transport glutamine and synthesize glutathione, contributing to improving the immune recognition by T cells and blocking the immune escape of tumor cells for metastatic tumor eradication. [Display omitted] [ABSTRACT FROM AUTHOR]

• Development of photodynamic degrader targeting breast cancer through EGFR. • Targeted degradation of EGFR using afatinib and ROS produced in situ. • EGFR inhibition mediated PD-L1 downregulation to reverse immunosuppression. • Immunogenic induction and intensive immune activation for metastatic tumor eradication. Spatiotemporal downregulation of immune checkpoint provides a promising strategy to activate anti-tumor immunity. In this work, a breast cancer targeted photodynamic degrader (designated as EIpro) is constructed to activate immunotherapy through EGFR degradation mediated PD-L1 downregulation. To be specific, we develop a chimeric peptide, comprising the photosensitizer Protoporphyrin IX (PpIX) and EGFR targeting peptide (QRHKPRE), to encapsulate an EGFR inhibitor afatinib (AFA) forming nanomicelle, namely EIpro. EIpro has a favorable stability and uniform nanosize distribution, preferring to accumulate in EGFR overexpressed breast cancer cells to amplify the chemotherapeutic effect and photodynamic elimination behavior. More interestingly, photodynamic therapy (PDT) produced reactive oxygen species (ROS) is able to damage breast cancer cells and induce immunogenic cell death (ICD) to release tumor associated antigens (TAAs), thereby degrading the nearby EGFR to downregulate PD-L1 and activate anti-tumor immunity. Beneficially, the multi-synergistic effects of EIpro show a robust therapeutic efficacy against primary and metastatic breast cancer with negligible systemic toxicity. This work provides a spatiotemporal strategy for protein degradation, which might inspire the development of sophisticated nanomedicine for effective tumor treatment. [ABSTRACT FROM AUTHOR]

• Construction of a stable ternary biomedicine without extra drug excipient. • Upregulating NLRP3 to promote PDT induced cell pyroptosis. • Immune activation by pyroptosis induction and IDO inhibition for tumor inhibition. The development of immunotherapy is seriously limited by the insufficient tumor immunogenicity and immunosuppressive microenvironment. Pyroptosis is a new form of immunogenic cell death (ICD) associated with the gasdermin protein family, which has received increasing attention as a promising approach to activate antitumor immunity. Herein, we construct a ternary biomedicine (CNS) based on the self-assembly of photosensitizer chlorine e6 (Ce6), NLG919 (NLG) and simvastatin (Sim), which has a fairly high drug content, good stability and uniform morphology. Interestingly, the photodynamic therapy of CNS can generate reactive oxygen species (ROS) to induce intracellular oxidative stress, activating NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/Caspase-1 (Cas-1)/gasdermin D N-terminal domain (GSDMD-N) dependent pyroptosis. Further, Sim-mediated NLRP3 upregulation will also promote cell pyroptosis to activate ICD and stimulate immune responses. Benefiting from NLG-induced indoleamine 2,3-dioxygenase (IDO) inhibition, CNS is capable of improving the immunosuppressive microenvironment to enhance immunotherapy. Consequently, the pyroptosis induction synergized with IDO inhibition of CNS exhibits excellent antitumor immune activities, as evidenced by enhancing DCs maturation and effector memory T cells frequency, which significantly inhibit tumor growth and metastasis. This proposal of self-delivery ternary nanomedicine might open a new window to construct drug delivery systems for pyroptosis activated immunotherapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Self-delivery immune adenosine effector (iMade) is fabricated through the self-assembly of pyropheophorbide-a and imaradenant without drug excipients. • Photodynamic therapy of iMade can destroy primary tumor cells to initiate immunogenic cell death (ICD) and trigger the burst release of danger related molecular patterns (DAMPs). • iMade can reduce the recognition of adenosine and A2AR for enhanced antigen presentation to activate anti-tumor immunity. • The activation of systemic immune response can suppress metastatic tumors with low systemic side effects. Therapy-induced immunogenic cell death (ICD) can trigger a burst release of immunostimulatory signals, but some of them can be converted into immunosuppressive factors to extensively restrict systemic anti-tumor immunity. In this work, a self-delivery im mune ad enosine e ffector (designated as iMade) is fabricated to eliminate metastatic tumors via photodynamic activated immunotherapy. Among which, nano-sized iMade is composed of pyropheophorbide-a (Pyro) and imaradenant (AZD) through drug self-assembly without extra excipients. Interestingly, the uniform iMade exhibits favorable stability and dispersity, helping improve the drug delivery efficiency in tumor tissues and cells. Mechanistically, the photodynamic therapy (PDT) of iMade can not only inhibit tumor cell proliferation, but also act as an ICD trigger to induce the burst release of danger related molecular patterns (DAMPs). Successively, AZD is released from iMade to reduce the recognition of adenosine and A2AR for enhanced antigen presentation. Ultimately, iMade is demonstrated to efficiently suppress the growth of primary tumor in vivo , and simultaneously activate systemic immune response to reduce metastatic tumors while cause no obvious systemic side effects. Such a simple but efficient strategy might provide a promising combinatory for spatiotemporal tumor treatment. [ABSTRACT FROM AUTHOR]

Self-delivery bioregulator (C-Moc) is developed through the self-assembly of chlorine e6 (Ce6) and mocetinostat (Moc) in the presence of DSPE-PEG 2000 via intermolecular forces. Carrier free C-Moc could not only inhibit primary tumor growth and induce immunogenic cell death (ICD) by photodynamic therapy (PDT), but also enhance the immune checkpoint-blockade (ICB) therapy by epigenetic reprogramming. [Display omitted] • High drug-loading capacity and favorable stability of self-delivery bioregulator. • Positive regulation of MHC-I and PD-L1 by HDAC1 inhibition. • Epigenetic reprogramming of C-Moc reversed immunosuppressive tumor microenvironment. • Primary and distant tumor inhibition by ICB therapy and PDT-induced ICD cascade. Photodynamic therapy (PDT) and immunotherapy have unique advantages for primary and metastatic tumor treatment. However, immunosuppressive tumor microenvironment (ITM) causes low immune responses and various degrees of therapeutic resistance. In this work, a self-delivery bioregulator (C-Moc) is developed for photodynamic amplified immune checkpoint-blockade (ICB) therapy by epigenetic reprogramming. To be specific, carrier-free C-Moc is prepared by the self-assembly of chlorine e6 (Ce6) and mocetinostat (Moc) in the presence of DSPE-PEG 2000 through electrostatic and hydrophobic interactions. Of note, nanosized C-Moc has an improved stability, cellular uptake and pharmacokinetics behaviors. Intravenously injected C-Moc prefers to accumulate at tumor site and then penetrate into tumor tissues upon light irradiation. Meanwhile, the initiated PDT would kill tumor cells for primary tumor inhibition and also induce immunogenic cell death (ICD) to activate antitumor immunity. More importantly, C-Moc is able to increase the expressions of MHC-I and PD-L1 to regulate ITM by epigenetic reprogramming, which would promote the recognition of immune system to MHC-I overexpressed tumor cells and enhance the ICB therapy of α-PD-L1. This photodynamic amplified ICB therapy of C-Moc shows a great superiority over the single treatment on primary and distant tumor suppression. [ABSTRACT FROM AUTHOR]

Tumor cells are characterized by unlimited proliferation and escape of immune clearance, which are closely associated with the down regulation of surface antigens. In this work, a carrier free photodynamic modulator (CeTaz) is developed to improve immunosuppressive tumor microenvironment and promote the recognition of tumors by T cells by epigenetic reprogramming. Specifically, CeTaz is assembled by chlorine e6 (Ce6) and tazemetostat (Taz) through intermolecular interactions. Upon light irradiation, CeTaz is able to promote the generation of reactive oxygen species (ROS) for a robust photodynamic therapy (PDT) to inhibit localized tumor growth. Meanwhile, the PDT also induces immunogenic cell death (ICD) to initiate immune response, leading to the activation of effector T cells. More importantly, CeTaz could inhibit the epigenetic regulator of EZH2 to suppress the methylation of H3K27, which would promote tumor cells to express MHC-I and release CXCL10. Consequently, the epigenetically reprogrammed tumor cells are readily recognized by effector T cells to enhance the antitumor immunity. Results indicate that the PDT activated immunotherapy of CeTaz could simultaneously inhibit the growth of primary and distant tumors with a low system toxicity. This study would advance the development of carrier free nanomedicine for precise treatment of metastatic tumor. [ABSTRACT FROM AUTHOR]

• Self-delivery nanomedicine of PyroR was prepared without drug-excipients. • PyroR could enhance the stability and facilitate the delivery of photosensitizers and TLR agonists. • Photodynamic therapy (PDT) of PyroR could efficiently inhibit primary tumor growth and initiate immunological cascade. • PryoR could repolarize M2 macrophages into M1 phenotype for immunotherapy against metastatic tumors. Immunotherapy is a promising clinical treatment strategy against malignant tumor metastasis, however, it often shows an inadequate efficacy owing to the immunosuppressive tumor microenvironment (ITM). Herein, we develop a self-delivery re-educator to induce immunogenic cell death (ICD) and macrophage polarization for photodynamic therapy (PDT) and immunotherapy against breast cancer. To be specific, the self-delivery re-educator (designated as PyroR) is prepared by the self-assembly of the photosensitizer pyropheophorbide-a (Pyro) and TLR agonist resiquimod (R848). Without any carriers, nanosized PyroR exhibits high drug contents and could avoid the side effects raised by excipients. After intravenous administration, PyroR could generate a lot of reactive oxygen species (ROS) for PDT against primary tumor in the presence of light irradiation. Meanwhile, PDT triggered ICD cascade would promote dendritic cells (DCs) maturation and activate cytotoxic T lymphocytes (CTLs) for immunotherapy against distant and metastatic tumors. More importantly, R848 is able to polarize macrophages from M2 to M1 phenotype, which would improve the ITM to enhance antitumor immunity. Consequently, the PDT-initiated immunotherapy of PyroR demonstrates significant inhibition effects on primary, distant and metastatic tumors while causes a minimal system toxicity. This self-delivery re-educating strategy would shed light on constructing carrier-free nanomedicine for treatment of malignant tumors. [ABSTRACT FROM AUTHOR]

Amplifying oxidative stress to break intracellular redox homeostasis could accelerate tumor cell death. In this work, a self-delivery oxidative stress amplifier is developed for chemotherapy sensitized immunotherapy. By virtue of the π-π stacking and coordination effect, copper ions (Cu2+), doxorubicin (DOX) and NLG919 are able to self-assembly into the nanosized oxidative stress amplifier (designated as Cu-DON) with a favorable stability and a biocompatibility. Intravenously administrated Cu-DON could effectively accumulate and penetrate into tumor tissues for cellular uptake. Subsequently, the GSH-responsive DOX release will initiate the immunogenic chemotherapy (IC) for primary tumor inhibition. Moreover, Cu2+-mediated GSH consumption and DOX-triggered oxidative stress could cause the intracellular redox imbalance, contributing to immunogenic cell death (ICD) response. Further, the concomitant release of NLG919 would inhibit indoleamine 2,3-dioxygenase 1 (IDO-1) to reverse immunosuppressive tumor microenvironment (ITM) for enhanced immunotherapy. Consequently, this self-delivery oxidative stress amplifier greatly restrains the growth of primary, distant as well as rechallenged tumors by chemotherapy sensitized immunotherapy, which would shed light on the development of combination therapy to block tumor growth and metastasis in clinic. [ABSTRACT FROM AUTHOR]