Search Results (174)

Photodynamic therapy (PDT) combines a photosensitizer (PS), light, and molecular oxygen to generate cytotoxic reactive species, but nominally similar regimens can produce different biological responses because prescribed inputs do not directly specify the biologically active exposure state. Here, this intermediate state is treated as a multidimensional profile defined by PS localization and photoactive availability, the intratissue light field, oxygen dynamics, and vascular conditions at illumination. The relative contributions of direct tumor-cell injury, vascular damage, inflammatory signaling, and adaptive immune modulation also depend on drug–light interval (DLI), treatment sequence, vascular architecture, and tumor–host context. This critical narrative review applies a parameter–exposure state–mechanism–endpoint framework to oncologic PDT. It distinguishes spatially restricted primary photochemical injury from downstream multicellular effects and appraises the evidentiary thresholds for immunogenic cell death (ICD) and systemic immune claims. It also proposes reporting considerations and translational priorities to improve study comparability. PDT mechanisms should be interpreted against measurable treatment parameters rather than presumed from a PS label or prescribed dose alone. Full article

HMGB-1 is an alarmin representative of DAMP playing a central role in immunogenic cell death (ICD), a necessary condition in the dialog established between dying tumor cells and the immune system during some anticancer therapies. Therefore, early screening for ICD inducers represents a major priority in drug development today. In this work, we investigated the effect elicited by the clinical-grade CIGB-300 peptide, which impairs Protein Kinase CK2-mediated phosphorylation and other CK2 signaling connected kinases. Here, HMGB-1 extracellular release was investigated in an 18-cell line panel from blood malignancies, uterine-cervical cancer and NSCLC treated with CIGB-300 at equipotent doses (IC₅₀) over 24 h. Interestingly, CIGB-300 treatment upregulated the HMGB-1 protein levels at the culture supernatant in most of the cell lines (p = 0.01) and fold-change increases ≥ 2 were associated with intrinsic cell line sensitivity towards CIGB-300’s cytotoxic effect. However, the HMGB-1 release by CIGB-300 was context-specific with clear induction on blood and uterine-cervical cancer cells and a diffused response pattern in NSCLC. Importantly, CIGB-300 treatment of blood cancer patients enrolled in a Phase I study induced plasma HMGB-1 alarmin in 4 out of 7 subject who received the entire treatment plan. Altogether, our data reveal for the first time that CIGB-300 treatment is able to induce extracellular HMGB-1 release in vitro and in vivo which could be indicative of ICD induction in some kinds of tumors; furthermore, the induction of extracellular HMGB-1 alarmin as a putative CIGB-300 response biomarker merits further investigation. Full article

Focused ultrasound (FUS) comprises a diverse group of non-invasive, non-ionizing acoustic technologies that have evolved from tools for localized tissue destruction into platforms capable of influencing complex biological processes. In oncology, growing evidence suggests that the effects of focused ultrasound extend beyond direct tumor treatment to include modulation of the tumor microenvironment and anti-tumor immunity. This review examines the major FUS modalities currently under investigation for cancer therapy, including high-intensity focused ultrasound (HIFU), intrinsic threshold histotripsy, boiling histotripsy, shock-scattering histotripsy, and low-intensity focused ultrasound (LIFU), with emphasis on the distinct physical mechanisms that underlie their biological effects. Although these modalities differ in how they interact with tissue, they share the capacity to alter tumor biology through changes in antigen availability, inflammatory signaling, and immune cell activity. These responses have been associated with enhanced immune recognition of tumors, remodeling of immunosuppressive microenvironments, and improved therapeutic responsiveness in preclinical and emerging clinical studies. As interest in focused ultrasound continues to expand, understanding the relationship between modality-specific bioeffects and downstream immune outcomes has become increasingly important. Collectively, the literature highlights focused ultrasound as a versatile therapeutic platform capable of linking precise local intervention with broader biological and immunological consequences, supporting its continued development as both a tumor-directed and immune-modulating strategy in cancer therapy. Full article

Background: The highly heterogeneous and dynamically evolving tumor microenvironment leads to the development of drug resistance and recurrence in traditional therapies. Although immunotherapy demonstrates unique advantages, its clinical utility remains constrained by the suboptimal immunogenicity and the limited effect of monotherapy. Herein, a hybrid drug delivery system based on a spatiotemporal hierarchical controlled-release strategy was proposed to achieve dual immunotherapy with immune checkpoint blockade (ICB) and immunogenic cell death (ICD) to promote synergistic anti-tumor therapy. Methods: A liposome–micelle hybrid drug delivery system (RUT-RPP-LP) was constructed using a lipid bilayer composed of dioleoyl phosphatidylethanolamine/hemisuccinyl cholesterol to encapsulate rutin (RUT) and to form an inner cavity-encapsulated resveratrol micelle (RPP). RUT-RPP-LP was characterized, and its pH sensitivity and release behavior were investigated. Subsequently, a colon cancer tumor-bearing mouse model was constructed to evaluate the in vivo targeted anti-tumor effect and biological safety. On this basis, the combined mechanism of ICB and ICD was preliminarily explored. Results: RUT-RPP-LP possessed excellent formulation characteristics, stability, and biocompatibility, achieving graded controlled release of drugs via responding to the TME and lysosomal acidity, respectively. Obviously, RUT-RPP-LP could specifically target the tumor site, induce the occurrence of ICD, and simultaneously block the PD-1/PD-L1 immune checkpoint signaling pathway, thereby enhancing the function of T cells and inducing apoptosis of tumor cells. Conclusions: The RUT-RPP-LP based on the hierarchical controlled-release strategy exerted a spatiotemporally coordinated enhancement of anti-tumor immunity, and may provide a novel combinatorial approach to overcome the low response of immunotherapy in solid tumors. Full article

Background: Generating personalized anti-tumor immune responses remains a primary objective of precision oncology, yet conventional autologous platforms face critical biological and logistical constraints. While current research modifies allogeneic lines to evade host clearance, this perspective outlines a translational framework designed to leverage host-donor incompatibility as an active immunomodulatory asset to remodel the solid tumor microenvironment (TME). The framework proposes expanding a systemic pool of circulating, allo-specific host type 1 helper (Th1) memory cells via iterative intradermal injections of completely mismatched, activated donor Th1 cells, followed by a systemic intravenous rechallenge to provoke a controlled host-versus-graft (HvG) rejection response. Rapid intravascular clearance of donor cells is hypothesized to drive a transient, Type 1 cytokine wave that activates host effector populations via bystander pathways, promoting their extravasation into the tumor stroma to induce immunogenic cell death (ICD). This paradigm is contextualized by Phase 2B data in refractory microsatellite stable (MSS) metastatic colorectal cancer, where a dual-route allogeneic Th1 regimen demonstrated a median overall survival (OS) signal of 16.4 months despite an 89.5% conventional radiological progression rate. Ultimately, this framework provides a predictable, non-engineered conceptual mechanism to elicit a patient-specific adaptive immune response without ex vivo customization. Full article

Nanosecond electric pulses (nsEPs) are an emerging pulsed-power technology with unique bioelectric characteristics distinct from conventional long-pulse electroporation. As a tunable physical modality, nsEPs can modulate intracellular structures, membrane dynamics, and signaling pathways. Increasing evidence supports nsEPs as a promising non-thermal tumor ablation approach due to their high spatial precision, preservation of critical tissue structures, and minimal adverse effects. One of the most significant discoveries associated with nsEP tumor ablation is the induction of potent systemic antitumor immunity, particularly in situ vaccination (ISV) effects and, in some cases, abscopal effects against distant untreated tumors. Substantial evidence demonstrates that nsEPs can function as authentic immunogenic cell death (ICD) inducers by promoting the release of damage-associated molecular patterns (DAMPs), including calreticulin (CRT), ATP, and HMGB1. These events facilitate dendritic cell activation, antigen presentation, and the generation of long-term antitumor T-cell immunity. In addition to enhancing tumor immunogenicity, nsEPs profoundly remodel the tumor microenvironment (TME), including disruption of tumor vasculature, reduction in immunosuppressive cell populations, and alteration of stromal components. Emerging studies further suggest that nsEPs act as electric metabolic modulators capable of influencing mitochondrial function, calcium signaling, and metabolism-associated signaling pathways. Current evidence indicates that the immunological outcomes induced by nsEPs are highly dependent on pulse parameters, waveform characteristics, and tumor type. Despite its considerable therapeutic promise, the development of nsEP-induced ISV immunotherapy faces several important challenges, including standardization and optimization of pulse protocols, identification of critical molecular and cellular targets, and clarification of tumor- and cell-type-specific responses. Addressing these challenges through multidisciplinary collaboration and advanced technologies, including multi-omics, spatial analysis, and computational modeling, may accelerate the development of next-generation bioelectric immunotherapies for cancer treatment. Full article

Background: The immunosuppressive tumor microenvironment (TME), driven by the CD39-mediated conversion of immunostimulatory ATP to immunosuppressive adenosine (ADO), limits cancer immunotherapy. Research design and methods: Here, we developed a nanoparticle (NP) for combined chemo-immunotherapy by co-delivering the ICD inducer doxorubicin (DOX) and a CD39 inhibitor (ARL67156). The amphiphilic polymer PEG2k-b-P(DMAEMA-co-DPAEMA)-b-PTDMAEMA self-assembled into NPs with stable drug loading and rapid, pH-triggered drug release in the acidic TME. Results: In vitro, NPs@DOX induced immunogenic cell death (ICD) and ATP release, while NPs/ARL effectively inhibited CD39. The co-loaded NPs (NPs@DOX/ARL) synergistically enhanced extracellular ATP accumulation by combining increased release with decreased degradation, leading to superior dendritic cell maturation. In vivo, NPs@DOX/ARL demonstrated enhanced tumor accumulation, significant tumor growth inhibition, and robust activation of anti-tumor T-cell immunity. Conclusions: This work presents a promising nanoplatform that targets the ATP-ADO axis to amplify ICD and reverse immunosuppression for enhanced cancer immunotherapy. Full article

Background: Photodynamic therapy (PDT) leading to immunogenic cell death (ICD) may serve as a promising basis for the development of antitumor therapeutic strategies. However, the mechanisms of action of photoinduced ICD in primary tumor cultures, including human glioma, remain unexplored. Methods: In the present study, the features of regulated cell death induced by photodynamic therapy using a previously described ICD inducer, porphyrazine III (pz III), were investigated. Cell death was studied in 7 primary cultures of high-grade human gliomas (astrocytomas, oligodendrogliomas, and glioblastomas). Results: Accumulation of porphyrazine III was observed in the endoplasmic reticulum (ER), Golgi apparatus, lysosomes, and mitochondria; however, the distribution of the photosensitizer varied across different cultures. A narrow concentration window of porphyrazine III was established to effectively reach IC85, primarily inducing ferroptosis with contributions from apoptosis and necroptosis accompanied by superoxide anion generation and mitochondrial dysfunction. Conclusions: Given the immunogenic potential of ferroptosis, apoptosis and necroptosis we hypothesize that the induction of PDT using porphyrazine III in glioma will trigger immunogenic cell death. Full article

Manganese-based nanomaterials have been novel multifunctional platforms in tumor immunotherapy because of their tunable multivalent states, biocompatibility, and multi-stimulus responsiveness. Current cancer treatments are insufficient and cause severe side effects; therefore, manganese-based nanomaterials are proposed in combination with immunotherapy to mitigate adverse effects. This review outlines the antitumor effects mediated by four key mechanisms: (1) activation of the cGAS-STING immune signaling pathway, (2) direct activation of immune cells, (3) induction of immunogenic cell death (ICD), and (4) modulation of the tumor microenvironment. These approaches are broadly categorized into two types: monotherapy and multimodal combination therapy. Monotherapy encompasses three specific modalities: (1) direct use as a Stimulator of Interferon Genes (STING) agonist, (2) vector-mediated targeted drug delivery, and (3) mediation of chemodynamic therapy to generate reactive oxygen species, thereby inducing ICD. Multimodal combination therapy involves synergistic integration with traditional or emerging treatment modalities, including chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy, and low-level light therapy, as well as multimodal combination treatment methods. It significantly enhances the antitumor efficacy of traditional therapies through immunostimulation, thus achieving synergistic breakthroughs in treatment efficiency and survival rate. Collectively, the multifunctional integration of manganese-based materials is a novel strategy for developing “self-adjuvant” immunotherapeutic platforms and investigating the clinical translation potential. Full article

The overexpression of hypoxia-inducible factor-1α (HIF-1α) suppresses STING signaling and modulates lipid metabolism in tumor cells, leading to abnormal lipid droplet (LD) accumulation. Herein, we constructed a manganese dioxide (MnO₂)-based nanomotor (HMIP@A). HMIP@A depletes intracellular hydrogen peroxide (H₂O₂) and glutathione (GSH) to generate oxygen (O₂), reactive oxygen species (ROS), and manganese (Mn²⁺). A dual strategy of “oxygen supplementation” and “small-molecule inhibition” synergistically downregulates HIF-1α, thereby suppressing LD biogenesis. This process sensitizes tumor cells to ROS, leading to severe DNA damage. Released Mn²⁺ and damaged DNA synergistically activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In vitro, HMIP@A markedly increases ROS production, lipid peroxidation (LPO), and DNA damage, thereby inducing tumor cell death, immunogenic cell death (ICD), and dendritic cell (DC) maturation. Furthermore, HMIP@A exhibits excellent penetration in tumor spheroids. Overall, this study provides a theoretical basis for the design of nanomedicines through a strategy integrating metabolic intervention, oxidative damage sensitization, and immune activation. Full article

This systematic review examines the emerging interplay between ferroptosis and disulfidptosis, two distinct forms of regulated cell death (RCD) centered on the SLC7A11 (also known as xCT)-mediated metabolic paradox. Traditionally recognized as a potent anti-ferroptotic factor, SLC7A11 imports cystine for glutathione synthesis to neutralize iron-dependent lipid peroxidation. However, the discovery of disulfidptosis identifies SLC7A11 as a metabolic liability, representing a paradigm shift in our understanding of cellular antioxidant defense. This discovery reveals a transformative vulnerability in SLC7A11-overexpressing cells, shifting the focus from conventional survival mechanisms to the consequences of catastrophic structural collapse. Beyond metabolic exhaustion, this review highlights the role of metal dyshomeostasis as a primary driver, spanning from iron-catalyzed ferroptosis to copper-mediated metabolic interference. This conceptual framework redefines the SLC7A11 axis as a targetable “double-edged sword” in therapy-resistant malignancies. Clinical synthesis of multi-omic gene signatures, such as the disulfidptosis- and ferroptosis-related gene prognostic score (DRGPS) and the ferroptosis- and disulfidptosis-related gene (FDRG) scores, demonstrates their robust value in prognostic stratification and in predicting immunotherapy response across malignancies, including lung adenocarcinoma and hepatocellular carcinoma. Furthermore, we evaluate the capacity of disulfidptosis to prime immunogenic cell death (ICD) and remodel the immunosuppressive tumor microenvironment to bypass chemoresistance. By integrating mechanistic insights with clinical data, this review provides a comprehensive framework for targeting the SLC7A11 axis as a transformative therapeutic vulnerability in precision oncology. Full article

Background: Modern oncology views immune system dysfunction as a key factor in carcinogenesis. The induction of immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immunity, represents a promising therapeutic strategy. Damage-associated molecular patterns (DAMPs) play a central role in this process. This review aims to summarize current knowledge of DAMPs, their release mechanisms during ICD, their classification, and their prognostic and therapeutic significance in antitumor immunity. Methods: We systematically reviewed and synthesized literature published in Pubmed and Google Scholar on ICD and DAMPs, focusing on distinct forms of DAMPs which were categorized based on recognition mechanisms (five classes) and cellular origin (extracellular, mitochondrial, nuclear, and cytosolic). Key molecules, their receptors, downstream signaling pathways, and clinical associations were analyzed. Results: The spatiotemporally coordinated release of the pattern of DAMPs promotes dendritic cell maturation, antigen presentation, activation of cytotoxic T lymphocytes, and elimination of tumor cells. DAMPs can exhibit a dual role: they are able to induce sterile inflammation essential for antitumor immunity, but may also contribute to metastasis and chronic inflammation. Among all DAMPs, high-mobility group box 1 (HMGB1, a nuclear DAMP) and calreticulin (CRT, a cytosolic protein) demonstrate the greatest prognostic value. Other DAMPs (e.g., extracellular matrix components, uric acid) act as signal amplifiers during various forms of cell death. Conclusions: Understanding the spatiotemporal dynamics of DAMP release is critical for activating immune responses against malignant cells. Monitoring DAMPs may improve patient stratification, predict therapeutic responses, and enable personalized immunotherapeutic strategies. Further investigation of ICD mechanisms and DAMP release represents a fundamental basis for developing novel anticancer therapies. Full article

Background: Photodynamic therapy (PDT) has emerged as a powerful minimally invasive modality for cancer treatment. However, its efficacy as a monotherapy is often limited by oxygen dependence and limited light penetration. Combining PDT with systemic anticancer drug therapies offers a promising strategy to achieve synergistic effects and overcome resistance. Objective: This review aims to provide a systematic analysis of the mechanisms and clinical potential of combining PDT with chemotherapy, targeted therapy, and immunotherapy, focusing on recent advancements and nanotechnology-based delivery systems. Methods: A comprehensive literature search was performed using PubMed and Scopus databases. The analysis focused on peer-reviewed studies published over the last 10 years addressing synergistic molecular pathways, co-delivery nanoplatforms, and clinical trial outcomes. Results: The combination of PDT with chemotherapy enhances drug accumulation via vascular photosensitization and can overcome multi-drug resistance. Integration with immunotherapy, particularly immune checkpoint inhibitors and tumor vaccines, triggers immunogenic cell death (ICD), leading to systemic antitumor responses. Nanotechnology provides a versatile platform for the targeted co-delivery of photosensitizers and pharmacological agents, significantly reducing systemic toxicity. Conclusions: Combined PDT–drug regimens demonstrate superior therapeutic efficacy compared to monotherapies. Future clinical translation requires the standardization of dosimetry and the development of multifunctional nanomedicines to enable personalized treatment protocols. Full article

Metal ion-based chemo-immunotherapy is often limited by rigid intracellular metal homeostasis, insufficient reactive oxygen species (ROS) accumulation, and an immunosuppressive tumor microenvironment (TME). To overcome these limitations, we engineered an ATP-responsive, core–shell bimetallic nanoreactor (Cu/ZIF@PDA, termed CZP) featuring a precisely controlled ~25 nm biomimetic polydopamine (PDA) coating. Triggered by elevated tumoral ATP levels, CZP undergoes coordination-induced disassembly and promotes oxidative stress amplification. Specifically, the PDA shell acts as a superoxide dismutase (SOD) mimetic to continuously supply H₂O₂, fueling Cu²⁺-mediated Fenton-like reactions to unleash highly toxic hydroxyl radicals (•OH) while aggressively depleting the intracellular glutathione (GSH) pool. This irreversible oxidative damage, coupled with Zn²⁺-induced mitochondrial dysfunction, triggers profound mitochondrial DNA (mtDNA) leakage. Crucially, this cytosolic DNA robustly activates the cGAS-STING signaling axis, driving a massive surge in immunogenic cell death (ICD) and significantly promoting dendritic cell (DC) maturation. Furthermore, CZP markedly inhibited primary tumor growth in vivo and showed protection in a tumor re-challenge model, accompanied by enhanced dendritic cell maturation. These findings support the potential of this ATP-responsive bimetallic nanoplatform to promote antitumor immune activation. Full article

Oncolytic viruses represent a paradigm-shifting approach to cancer immunotherapy, functioning as in situ vaccines that convert immunologically “cold” tumors into “hot” tumors through induction of immunogenic cell death (ICD). Despite the clinical success of checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), many patients exhibit primary or acquired resistance due to insufficient tumor immunogenicity and exclusion of tumor-infiltrating lymphocytes. Oncolytic viruses address this limitation by selectively replicating in tumor cells, inducing robust ICD characterized by four cardinal hallmarks: calreticulin exposure, ATP secretion, HMGB1 release, and type I interferon production. This review systematically examines the molecular mechanisms underlying virus-induced ICD, compares DNA virus platforms (Vaccinia, HSV-1, Adenovirus) with RNA virus platforms (Coxsackieviruses A21, A11, and B3), and analyzes clinical trial data demonstrating synergistic efficacy when combined with checkpoint inhibitors. Notably, RNA viruses generate higher type I interferon responses compared to DNA viruses, correlating with superior clinical outcomes. Coxsackievirus A21 combined with pembrolizumab achieved a 47% objective response rate in melanoma in the CAPRA trial, representing notable efficacy exceeding either monotherapy. Coxsackievirus A11 demonstrates exceptional selectivity for thoracic cancers through ICAM-1-dependent receptor tropism and potent immunogenic cell death induction. Japanese researchers have pioneered microRNA-targeted Coxsackievirus B3, achieving cardiac safety attenuation while preserving complete oncolytic potency and ICD-inducing capacity. This comprehensive analysis synthesizes molecular mechanisms, platform comparisons, clinical efficacy data, and translational challenges to guide future development of oncolytic virotherapy as a cornerstone of cancer immunotherapy. Full article