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A tricomponent immunoactivating nanomedicine called TIN is developed to downregulate PD-L1 and repolarize tumor-associated macrophages by inhibiting the activity of EGFR and CSF-1R. TIN restores the immune recognition of T cells and the phagocytosis of macrophage to reshape the immunosuppressive tumor microenvironment, contributing to a robust immunotherapeutic effect against colorectal cancer. [Display omitted] The unsatisfactory immunotherapeutic responses are primarily attributed to the insufficient immune recognition and the presence of an immunosuppressive tumor microenvironment (ITM). This study focuses on the development of a tricomponent immunoactivating nanomedicine called TIN that combines a photosensitizer, an inhibitor of epidermal growth factor receptor (EGFR) and a CSF-1R inhibitor to enable photodynamic immunotherapy by downregulating PD-L1 expression and repolarizing tumor-associated macrophages (TAMs). TIN is designed to facilitate the drug delivery and target specific pathways involved in tumor progression. By inhibiting the activity of EGFR and CSF-1R, TIN reduces PD-L1 expression on tumor cells and induces the TAMs polarization to M1 phenotype, restoring the immune recognition of T cells and the phagocytosis of macrophage to reshape the immunosuppressive microenvironment. Additionally, the photodynamic therapy (PDT) of TIN can greatly destroy the primary tumor and trigger immunogenic cell death (ICD). Importantly, the immune checkpoint blockade effect of TIN can enhance the immune response of PDT-induced ICD for metastatic tumor treatment. This study presents a self-assembling strategy for the development of an all-in-one nanomedicine, effectively integrating multiple therapeutic modalities to provide a comprehensive and systemic approach for tumor suppression. [ABSTRACT FROM AUTHOR]

As a first studied and generally accepted programmed cell death regulator, Bcl-2 has been identified to overexpress in many types of cancer promoting tumor proliferation and progression. Herein, inspired by drug self-delivery systems, a self-assembled nanomedicine (designated as GosCe) was designed based on the hydrophobic interaction between chlorin e6 (Ce6) and gossypol (Gos). Without extra carriers, GosCe exhibited high drug loading rates, favorable size distribution, and a long-term stability at aqueous phase. More importantly, GosCe could be internalized by tumor cells more effectively than free Ce6, which brought about its multiple toxicity. Upon intravenous injection, GosCe preferred to accumulate in tumor site through enhanced permeability and retention (EPR) effect. After cellular internalization, Gos contributed to increasing the lethality of Ce6-guided photodynamic therapy (PDT) by down-regulating Bcl-2 protein expression and inducing endoplasmic reticulum (ER) stress. Both in vitro and in vivo investigations indicated that the Gos-assisted PDT greatly inhibit cell proliferation and tumor growth. This study might shed light on developing carrier free nanomedicine for PDT-based synergistic tumor therapy. Metabolic abnormalities of tumor cells create defensive microenvironments which induce a therapeutic resistance against photodynamic therapy (PDT). Among which, the upregulated B-cell lymphoma (Bcl-2) in tumors could inhibit the PDT-induced cell apoptosis. In this work, a self-delivery nanomedicine (GosCe) was developed based on a Bcl-2 inhibitor and photosensitizer through intermolecular interactions, which had favorable size distribution, high drug contents and improved drug delivery efficiency. Importantly, GosCe increased the PDT efficacy by Bcl-2 inhibition and endoplasmic reticulum stress elevation. Thus, GosCe greatly inhibited the tumor growth while caused a reduced side effect in vivo. This carrier free nanomedicine with tumor microenvironment regulation would advance the development of photodynamic nanoplatform in tumor treatment. [Display omitted]. [ABSTRACT FROM AUTHOR]

Antioxidant-defense systems of tumor cells protect them from oxidative damage. Herein, a carrier-free nanomedicine is developed based on chlorine e6 (Ce6) and coniferyl ferulate (Con), which inhibits glutathione S-transferase (GST) activity to hamper antioxidant systems and amplify intracellular oxidative stress for enhanced photodynamic therapy. [ABSTRACT FROM AUTHOR]

A chlorine e6 (Ce6) and curcumin (Cur) based self-delivery nanomedicine (CeCu) is prepared for chemotherapy sensitized photodynamic therapy (PDT). The chemotherapeutic agent of Cur could inhibit the TrxR activity to destroy the cellular ROS-defence system for enhanced PDT, which provides synergistic effects for tumor precision therapy in consideration of the unfavorable tumor microenvironments. [ABSTRACT FROM AUTHOR]

As most solid tumors are characterized by a hypoxic microenvironment, enormous efforts have been made to develop strategies to fight hypoxia. This study shows that ivermectin (IVM), an antiparasitic drug, is able to alleviate tumor hypoxia by inhibiting mitochondrial respiration. We explore this to strengthen oxygen-dependent photodynamic therapy (PDT) using chlorin e6 (Ce6) as a photosensitizer. To synergize their pharmacological behaviors, Ce6 and IVM are encapsulated into stable Pluronic F127 micelles. The micelles are uniform in size and seem well-suited for the co-delivery of Ce6 and IVM. The micelles could passively target the drugs into tumors and enhance their cellular internalization. Most importantly, through mitochondrial dysfunction, the micelles reduce the oxygen consumption (making the tumor less hypoxic). Consequently, the production of reactive oxygen species would be increase which, in turn, improves the efficacy of PDT against hypoxic tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

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]

Tumor cells overexpress programmed cell death ligand 1 (PD-L1) to impede immune responses and escape immune elimination. Development of effective combination regimens to sensitize immunotherapy is promising but always challenging. Herein, a self-reinforced photodynamic immunostimulator (designated as PCS) is constructed for metastatic breast cancer treatment through simultaneous downregulation and blockade of PD-L1. Specifically, PCS is prepared by encapsulating signal transducer and activator of transcription 3 (STAT3) inhibitor (Stattic) into photosensitizer (protoporphyrin IX) modified PD-L1 blockade peptide (CVRARTR) through drug self-assembly. PCS can facilitate the targeted drug accumulation in PD-L1 overexpressed breast cancer cells to block PD-L1 and inhibit the phosphorylation of STAT3 to downregulate PD-L1. Moreover, PCS increases intracellular oxidative stress to show a robust anti-proliferation effect through photodynamic therapy (PDT), which also triggers an immunogenic cell death (ICD) to expose the immunostimulatory signals. Consequently, the efficient PD-L1 inhibition and robust PDT of PCS synergistically suppress the malignant growth of breast cancer, and concurrently activate the systemic anti-tumor immunity for metastatic inhibition with no obvious side effects. Such a photodynamic immunostimulator may provide an effective combination regimen for therapies activated immunotherapy against metastatic breast cancer. [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]