Gambogic acid and an NIR organic photothermal agent co-assembled nanoplatform to ignite immunogenic cell death / HSP90 suppression / ferroptosis for enhanced tumor mild-photothermal therapy.

CD38-targeted antibody-polymer drug conjugates for enhanced treatment of multiple myeloma.

Mitochondria-targeted iridium(III)-PF-06840003 conjugates: Apoptosis induction, IDO inhibition and ICD response.

Lattice-distorted two-dimensional Zr-based metal-organic frameworks for enhanced piezocatalytic-immunotherapy.

A hypoxia-responsive nanomedicine for cancer immunotherapy through ligand competition-induced dual-prodrug activation.

The Rh( i ) complex 3a with the 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene (dpp-bian) ligand induces type I immunogenic cell death (ICD), whereas the analogous Ir( i ) complex does not, revealing metal-specific immunogenicity.

A clinically inspired olsalazine-based metal-organic framework enables a universal nanodrugs platform for diverse disease.

A multimodal imaging nanobubble enhancing sonodynamic therapy by cell membrane disruption for effective anti-melanoma.

Tumor microenvironment-responsive CA@ZIF-8/MnO2 nanoreactor for self-reinforcing cascade chemodynamic therapy and immunomodulation.

Rationale: The efficacy of radiotherapy in triple-negative breast cancer (TNBC) is often limited by an immunosuppressive tumor microenvironment (TME), requiring high radiation doses that cause systemic toxicity. There is a critical need for theranostic strategies capable of guiding therapy and amplifying the efficacy of low-dose radiation. Methods: We developed a multifunctional organolutetium nanosensitizer (LSPA) for image-guided, low-dose radioimmunotherapy. Lutetium (Lu) serves as both a contrast agent for CT imaging and a radiosensitizer through the generation of reactive oxygen species (ROS). The LSPA nanoparticles were engineered to selectively accumulate in tumors and release their therapeutic payload in response to the acidic TME. Results: At a low 6 Gy X-ray dose, LSPA synergized with the PARP inhibitor Olaparib to induce extensive DNA damage. This activated the cGAS-STING pathway and remodeled the TME. The treatment promoted immunogenic cell death, dendritic cell maturation, and M1 macrophage repolarization. It also decreased regulatory T cells, leading to increased CD4+ and CD8+ T cell infiltration in both primary and metastatic tumors. Conclusion: This theranostic strategy suppressed primary and distant (abscopal) tumors, prevented recurrence, and established durable immune memory with low-dose irradiation. Our findings present a clinically translatable approach that combines a nanosensitizer with PARP inhibition to turn immunologically "cold" tumors into "hot" ones, thereby enhancing the efficacy of low-dose radioimmunotherapy while limiting systemic toxicity.

Breaking barriers in immunotherapy: harnessing ultrasound for enhanced drug delivery and immune activation.

Rationale: Nanotheranostics have attracted significant research attention for their potential in improving glioma management through integrated diagnostic and therapeutic functions. However, the limited capacity for dynamic structural transformation of current nanotheranostics in the tumor microenvironment (TME) restricts theranostic outcomes. Methods: Herein, we report a semiconducting polymer (SP)-based nanochanger (TM-P@SPN) that demonstrates aggregation-enhanced self-programable theranostics in orthotopic glioma upon glutathione (GSH) response. The TM-P@SPN is prepared using a SP as a triple-functional component (fluorescence probe, second near-infrared photoacoustic probe, and photothermal sensitizer), β-amyloid peptide domain (KLVFF)-linked PEG as an aggregation trigger switch, and transferrin modified manganese dioxide (TM) as a targeting theranostic agent. Results: Upon GSH response in the TME, the TM-P@SPN disassembles to release PEG and Mn (II), enabling SP-KLVFF-mediated hydrophobic aggregation through hydrogen bonding, which consequently enhances both photoacoustic imaging (PAI) and photothermal therapy (PTT). Meanwhile, the released Mn(II) can be utilized for T 1-weighted magnetic resonance imaging (MRI) and chemodynamic therapy (CDT). Moreover, both CDT- and PTT-induced immunogenic cell death effect and Mn(II)-activated STING pathway promote dendritic cells maturation, thereby triggering systemic immune effects. Conclusions: This TME-responsive nanochanger is successfully used for self-programable theranostics, including fluorescence imaging (FLI)-enhanced PAI-MRI and CDT-enhanced PTT-immunotherapy.

Rationale: Selective initiation of pyroptosis in malignant cells can amplify the immunological benefits of photodynamic therapy (PDT), but conventional photosensitizers (PSs) often lack tumor specificity and require complex subcellular targeting motifs. Here we describe a glutathione (GSH)-responsive PDT platform based on PSs that integrate fluorescence turn-on, GSH depletion, and restoration of reactive oxygen species (ROS) generation into a single molecular design. Methods: GSH-activated photosensitizers MTP-NO2 and NTP-NO2 were synthesized based on donor-acceptor structure, with their GSH-triggered activation, GSH depletion, ROS restoration, and caspase-1/GSDMD-mediated pyroptosis systematically demonstrated in 4T1 cells, while tumor accumulation, biodistribution, in vivo activation, and photodynamic antitumor efficacy of PSs nanoparticles were comprehensively assessed in 4T1 tumor-bearing mice through fluorescence imaging and immunohistochemical analyses. Results: Among a library of donor-acceptor scaffolds, the π-extended acene derivative NTP-NO2, equipped with a para-dinitrophenoxybenzyl pyridinium quencher, exhibited strong optical activation and ROS production upon reaction with elevated GSH in tumor cells. This dual action, antioxidant depletion and ROS restoration, triggered caspase-1/gasdermin-D-mediated pyroptosis, IL-1β/IL-18 release, and robust immunogenic cell death. Nanoparticle delivery of NTP-NO2 achieved high tumor accumulation, precise imaging, and pronounced antitumor efficacy in vivo. Conclusion: By exploiting tumor GSH overexpression-activated photodynamic therapy, the NTP-NO2 depletes GSH and promotes caspase-1/GSDMD pathway to trigger robust pyroptosis, eliciting inflammatory/immune responses both in vitro and in vivo. This chemically defined approach provides a PS design that unites selective activation, immune-stimulatory cell death, and precise photodynamic tumor ablation.

Multi-bioactive poly(amino acid)-metal-organic framework nanocomposite for reinforced cascading photodynamic immunotherapy of cancer.

Mitochondrion-targeted magnolol derivatives exert synergistic anticancer activity by modulating energy metabolism and tumor microenvironment.

A controllable self-amplifying oxidative stress strategy for boosting noninvasive sonodynamic therapy and synergistic immunotherapy.

ABSTRACT Checkpoint blockade immunotherapy emerges as a potential cure of cancer, but the monotherapy suffers from a low response rate in clinic. Photothermal therapy (PTT) that harvests light energy to ablate tumor is reported to activate tumor-specific immune response, meanwhile nitric oxide (NO) is considered to involve in immune regulation. Herein, we designed a multifunctional nanoplatform that enables photothermal-gas combination therapy by conjugating indocyanine green-thiol (ICG-SH) and s-nitrosoglutathione (GSNO) onto polyvinyl pyrrolidone (PVP)-coated gold nanoparticles (AIG). Upon near-infrared light (NIR) irradiation, AIG heats up the cancer cells and triggers NO release from GSNO, thus inducing apoptosis in the tumor. We found the combination of NO with photothermal treatment causes immunogenic cell death, which should synergize with checkpoint blockade immunotherapy. In the mouse colon cancer bilateral model, we observed complete eradication of light-irradiated tumors and suppression of distant untreated tumors in the AIG with anti-PD-1 (αPD-1) group. We detected significant increase of pro-inflammatory factors in serum, such as interferon- (IFN–γ), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) after PTT-gas-immunotherapy treatment, indicating the successful activation of the immune response. The improved immunogenicity caused by AIG with αPD-1 group allows for efficient antigen presentation, as evidenced by the increased infiltration of dendritic cells (DCs) into the tumor-draining lymph nodes (LNs). We also found promoted infiltration of CD8+ T cells in the untreated tumors in the AIG with αPD-1 group comparing to αPD-1 alone. Therefore, phototermal-gas-immune checkpoint blockade combination therapy represents a new promising treatment of metastatic cancer.

Immunotherapy (IT) and especially immune checkpoint blockade (ICB) changed the therapeutic approach in non-small cell lung cancer (NSCLC). Nevertheless, primary or secondary resistance and a percentage of long responders and survivors have been observed. The aim of this study is to gain a deeper understanding of the complex mechanisms of primary and secondary resistance to IT, involving tumor cells, the tumor microenvironment (TME), and the host, in order to find strategies to overcome it. With this aim in mind, a search for key words has been performed to identify relevant evidence in the literature. The most widely used approach is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect on the enhancement of immunogenic cell death. Since a dual role has been observed, a lot of questions are yet to be answered regarding the complex effect of these therapies, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, and the optimal RT volumes, sites, and dose/fractionation regimens to favor immune stimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors on immune or tumor cells are under evaluation. The huge potential of combination therapies becoming apparent. Questions regarding targets, selection of patients, and time and sequence of administration are yet to be answered, considering the complex mechanisms of resistance. Dynamic biomarkers to guide personalized treatment decisions are needed.

The therapeutic efficacy of ultrasound-based tumor therapy is greatly hampered by tumor hypoxia and an immunosuppressive microenvironment. To address this, a sonosensitizing nanoshuttle (DPPM@HA) was constructed by coencapsulating oxygen-carrying perfluocarbon (PFC) and the STING agonist DMXAA into PCN222-Mn metal-organic frameworks, followed by hyaluronic acid (HA) modification for tumor-targeted delivery. After systemic administration, DPPM@HA accumulated at tumor sites and was specifically internalized by tumor cells. Ultrasound (US) irradiation facilitated the liberation of oxygen from DPPM@HA to alleviate hypoxia and immune suppression, while adequate oxygen supply and the US-sensitization effects of Mn-TCPP in DPPM@HA jointly promoted the burst of cytotoxic reactive oxygen species (ROS), exacerbating US-induced tumor damage and eliciting severe immunogenic tumor cell death. Meanwhile, high-valence manganese in the frameworks consumed by glutathione and was reduced to Mn(II), facilitating the destruction of DPPM@HA to release the loaded DMXAA. The resultant Mn2+ synergized with DMXAA to provoke STING activation, intensifying downstream immune responses. Besides the suppression of the unilateral tumor by DPPM@HA-mediated sonodynamic immunotherapy, the synergy with immune checkpoint blockade further enhanced systemic antitumor immunity, achieving potent effects against distant tumors and metastases. Summarily, the proposed DPPM@HA-mediated sonodynamic immunotherapy offered a promising strategy for high-performance sonodynamic immunotherapy.

Breast cancer remains a major clinical challenge due to its high recurrence and metastatic potential. Here, we develop a multifunctional photothermal nanocomposite, GS@AM@M, integrating gold nanorods and mesoporous silica for synergistic photothermal-epigenetic immunotherapy. GS@AM@M exhibits excellent photothermal conversion efficiency under NIR-II (808 nm) irradiation, while its mesoporous framework enables efficient coloading of the DNA methyltransferase inhibitor 5-azacytidine (5-Aza) and the histone deacetylase inhibitor mocetinostat (MGCD). To enhance tumor targeting and immune evasion, the nanocomposite is camouflaged with macrophage-derived cell membranes. Upon NIR-II irradiation, GS@AM@M accumulates within tumors and enables controlled drug release. The combined therapy induces immunogenic cell death (ICD), promotes dendritic cell maturation, and activates cytotoxic CD8+ T cells. Meanwhile, epigenetic reprogramming of the MYC/Type I IFN signaling axis enhances CCL5 secretion, thereby recruiting and amplifying CD8+ T-cell responses. This synergistic mechanism effectively eradicates both primary and metastatic tumors while establishing durable immune memory to prevent recurrence. By integrating photothermal therapy, immunotherapy, and epigenetic modulation, GS@AM@M provides a potent and precise platform for comprehensive breast cancer treatment.