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The desirable curative effect in clinical immunotherapy has been challenging due to the immunosuppressive tumor microenvironment (TME) with high lactic acid (LA) metabolism in solid tumors. Although targeting metabolic reprogramming of tumor cells can restore the survival and function of immune cells in the TME, it is also plagued by insufficient immunogenicity. Herein, an activatable immunomodulatory nanoadjuvant CuSe/CoSe2@syrosingopine (CSC@Syro) is constructed for simultaneously relieving immunosuppressive TME and boosting tumor immune response. Specifically, CuSe/CoSe2(CSC) exhibits TME-activated glutathione (GSH) depletion and hydroxyl radical (•OH) generation for potential ferroptosis. Meanwhile, the remarkable photothermal conversion efficiency and elevated photocatalytic ROS level both promote CSC heterostructures to induce robust immunogenic cell death (ICD). Besides, the loaded syrosingopine inhibitor achieves LA metabolism blockade in cancer cells by downregulating the expression of monocarboxylate transporter 4 (MCT4), which could sensitize ferroptosis by intracellular milieu acidification and neutralize the acidic TME to alleviate immunosuppression. Hence, advanced metabolic modulation confers the potentiated immune infiltration of ICD-stimulated T lymphocytes and further reinforces antitumor therapy. In brief, CSC@Syro-mediated synergistic therapy could elicit potent immunogenicity and suppress tumor proliferation and metastasis effectually by integrating the tumor metabolic regulation and ferroptosis with immunotherapy.

The development of novel sonosensitizers with outstanding reactive oxygen (ROS) generation capacity and great biocompatibility poses a significant challenge for the clinical practice of sonodynamic therapy (SDT). In this work, hemoglobin (Hb) with natural metalloporphyrin was first shown to possess great potential as a sonosensitizer. Compared with traditional organic sonosensitizers, Hb had satisfactory sono-sensitizing efficiency because four the porphyrin molecules were separated by four polypeptide chains. This effectively avoided the problem of low ROS quantum yield caused by the stacking of hydrophobic porphyrins. Meanwhile, Hb is an efficient and safe oxygen carrier that may release O2at hypoxic tumors site, which improved tumor oxygenation and subsequently enhanced SDT efficacy. Therefore, Hb was integrated with zeolitic imidazolate framework 8 (ZIF-8) to form a nanoplatform that demonstrated a potent suppression effect on deep-seated tumors under ultrasound irradiation.

Chemodynamic therapy (CDT) relying on the transformation of endogenous hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (·OH) based on the catalysis of Fenton/Fenton-type reactions exhibits great potentiality for cancer treatment. However, the inadequate H2O2supply and intricate redox homeostasis in tumor microenvironment (TME) severely impair the efficacy of CDT. Herein, we design self-assembled 1,2-distearoyl-sn-glycero-3-phosphoethanolamine conjugated polyethylene glycol (DSPE-PEG)-modified Fe(III)-juglone nanoscale coordination polymers (FJP NCPs) as redox homeostasis disruptors for juglone-enhanced CDT. Responding to glutathione (GSH)-rich and acidic TME, the Fe2+/Fe3+-guided CDT and GSH consumption by Fe3+are activated, resulting in ·OH downstream and up-regulation of lipid peroxidation (LPO). In addition, the released juglone not only depletes GSH through Michael addition, but also elevates intracellular H2O2level for achieving ·OH further bursting. With the impressive efficiency of GSH exhaustion and reactive oxygen species (ROS) storm generation, ferroptosis and apoptosis are significantly enhanced by FJP NCPs in vivo. In brief, this facile and efficient design for versatile nanoscale coordination polymers presents a novel paradigm for effectively elevating CDT efficiency and tumor synergistic therapy.

Various hydrogels have been used for protein delivery in the treatment of human diseases. Nevertheless, it is always difficult to control the capture and release of multiple proteins in different regions and periods. This research successfully proves that multiple proteins can be captured and released from the aptamer-patterned hydrogel films with an adjustable release rate at a prospective time and in specific regions utilizing the complementary DNA strand of aptamers via photoclick chemistry and DNA hybridization. The hydrogel film is successfully applied to complex matrixes such as human serum and has excellent cytocompatibility. Thus, the aptamer-patterned hydrogel film will be a good candidate for controlled delivery of multiple proteins.

Compared with traditional photodynamic therapy (PDT), ultrasound (US) triggered sonodynamic therapy (SDT) has a wide application prospect in tumor therapy because of its deeper penetration depth. Herein, a novel MnSiO3-Pt (MP) nanocomposite composed of MnSiO3nanosphere and noble metallic Pt was successfully constructed. After modification with bovine serum albumin (BSA) and chlorine e6 (Ce6), the multifunctional nanoplatform MnSiO3-Pt@BSA-Ce6 (MPBC) realized the magnetic resonance imaging (MRI)-guided synergetic SDT/chemodynamic therapy (CDT). In this nanoplatform, sonosensitizer Ce6 can generate singlet oxygen (1O2) to kill cancer cells under US irradiation. Meanwhile, the loaded Pt has the ability to catalyze the decomposition of overexpressed hydrogen peroxide (H2O2) in tumor microenvironment (TME) to produce oxygen (O2), which can conquer tumor hypoxia and promote the SDT-induced 1O2production. In addition, MP can degrade in mildly acidic and reductive TME, causing the release of Mn2+. The released Mn2+not only can be used for MRI, but also can generate hydroxyl radical (∙OH) for CDT by Fenton-like reaction. The multifunctional nanoplatform MPBC has high biological safety and good anticancer effect, which displays the great latent capacity in biological application.

Although vaccine adjuvants are widely used in various preventive vaccines currently, for therapeutic cancer vaccines, they are still hindered by weak cellular immune responses. Here, a new concept of pyroptosis adjuvants (PTAVs) is proposed, and as a proof of concept, glucose oxidase (GOx)-loaded urchin-like manganese oxide (MnOx) as PTAVs with gram-scale production for exogenetic antigen-free tumor immunotherapy is reported. The obtained PTAVs dramatically generate reactive oxygen species (ROS) by cascade catalytic reactions to realize pyroptosis-induced in situ immune activation. Furthermore, PTAVs can more effectively inhibit tumor growth and pulmonary metastasis, suggesting favorable antitumor immune effects. This work is believed to provide a new scheme and inspiration for pyroptosis-mediated cancer treatments and be of great significance for the further development of cancer vaccine adjuvants.

Objective: To analysis the uptake of free MTX and MTX conjugated to tumor specific monoclonal antibody by target and non-target cells. Methods: The folate antagonist methotrexate (MTX) was conjugated to two monoclonal antibodies (Mab) directed against human chronic lymphocytic leukemia (CLL), Dal B01 and Dal B02, by an active ester method. Both conjugates were more cytotoxic toward the target tumor cell line D10-1 than to the non-target cell line MOLT-3, and Dal B02-MTX conjugate was more inhibitory to D10-1 cells than free MTX in a 6 h pulse exposure assay. Results: Drug uptake studies revealed that D10-1 cells took up much more Dal B01 and Dal B02-conjugated MTX than free MTX. The amounts of drug taken up by D10-1 cells incubated with Dal B01 and Dal B02-conjugated MTX were always 3 to 5-fold higher than that taken up by MOLT-3 cells, although the latter took up more drug when incubated with free MTX. Furthermore, tumor cells incubated with Dal B01 or Dal B02-conjugated MTX retained much larger amounts of drug for a prolonged period of time than those incubated with free MTX. Conclusion: The enhanced specific cytotoxicity of Dal B01 and Dal B02-MTX conjugates toward target tumor cells is therefore likely due to (I) delivery of larger amounts of MTX to target cells when the drug is conjugated to Mab; (ii) longer retention of Mab-conjugated MTX by target cells; and (iii) slow, prolonged release of MTX from the surface-bound or endocytosed conjugates, rendering them into a sustained release dosage form.

Dal B02, a murine monoclonal antibody against human chronic lymphocytic leukemia (CLL) was radioiodinated using chloramine T (Chl.T), Bolton-Hunter (B-H) or N-succinimidyl-p-iodobenzoate (PIB). The preparations had comparable radiochemical purity (> 97%) and immunoreactive fraction (65–80%) but the Chl.T-based product was most susceptible to deiodination and loss of immunoreactivity. After i.v. injection into CLL-xenografted nude mice, the preparations had identical patterns of clearance from the blood but the PIB-based product led to more radioactivity in liver and spleen and less in the thyroid compared to the other preparations. The Chl.T-based product showed loss of immunoreactivity in circulation and less tumor-localized radioactivity 168 h after administration. The differences between the B-H-based and PIB-based products were less impressive than between PIB-based and Chl.T-based products.