Explore the vast range of titles available.

Immunogenic cell death (ICD) is a form of regulated cell death (RCD) induced by various stresses and produces antitumor immunity via damage-associated molecular patterns (DAMPs) release or exposure, mainly including high mobility group box 1 (HMGB1), calreticulin (CRT), adenosine triphosphate (ATP), and heat shock proteins (HSPs). Emerging evidence has suggested that ionizing radiation (IR) can induce ICD, and the dose, type, and fractionation of irradiation influence the induction of ICD. At present, IR-induced ICD is mainly verified in vitro in mice and there is few clinical evidence about it. To boost the induction of ICD by IR, some strategies have shown synergy with IR to enhance antitumor immune response, such as hyperthermia, nanoparticles, and chemotherapy. In this review, we focus on the molecular mechanisms of ICD, ICD-promoting factors associated with irradiation, the clinical evidence of ICD, and immunogenic forms of cell death. Finally, we summarize various methods of improving ICD induced by IR.

Radiation therapy can potentially induce immunogenic cell death, thereby priming anti-tumor adaptive immune responses. However, radiation-induced systemic immune responses are very rare and insufficient to meet clinical needs. Here, we demonstrate a synergetic strategy for boosting radiation-induced immunogenic cell death by constructing gadolinium-hemin based nanoscale coordination polymers to simultaneously perform X-ray deposition and glutathione depletion. Subsequently, immunogenic cell death is induced by sensitized radiation to potentiate checkpoint blockade immunotherapies against primary and metastatic tumors. In conclusion, nanoscale coordination polymers-sensitized radiation therapy exhibits biocompatibility and therapeutic efficacy in preclinical cancer models, and has the potential for further application in cancer radio-immunotherapy. Radiotherapy has the potential to induce immunogenic cell death (ICD), however radiation-induced immune responses are often limited. Here the authors design gadolinium-based nanoscale coordination polymers to amplify radiation-mediated oxidative stress, promoting ICD and anti-tumor immune responses.

Extracorporeal photochemotherapy (ECP) is employed for the management of cutaneous T cell lymphoma (CTCL). ECP involves the extracorporeal exposure of white blood cells (WBCs) to a photosensitizer, 8-methoxypsoralen (8-MOP), in the context of ultraviolet A (UVA) radiation, followed by WBC reinfusion. Historically, the therapeutic activity of ECP has been attributed to selective cytotoxicity on circulating CTCL cells. However, only a fraction of WBCs is exposed to ECP, and 8-MOP is inactive in the absence of UVA light, implying that other mechanisms underlie the anticancer effects of ECP. Recently, ECP has been shown to enable the physiological differentiation of monocytes into dendritic cells (DCs) that efficiently cross-present tumor-associated antigens (TAAs) to CD8 + T lymphocytes to initiate cognate immunity. However, the source of TAAs and immunostimulatory signals for such DCs remains to be elucidated. Here, we demonstrate that 8-MOP plus UVA light reduces melanoma cell viability along with the emission of ICD-associated danger signals including calreticulin (CALR) exposure on the cell surface and secretion of ATP, high mobility group box 1 (HMGB1) and type I interferon (IFN). Consistently, melanoma cells succumbing to 8-MOP plus UVA irradiation are efficiently engulfed by monocytes, ultimately leading to cross-priming of CD8 + T cells against cancer. Moreover, malignant cells killed by 8-MOP plus UVA irradiation in vitro vaccinate syngeneic immunocompetent mice against living cancer cells of the same type, and such a protection is lost when cancer cells are depleted of calreticulin or HMGB1, as well as in the presence of an ATP-degrading enzyme or antibodies blocking type I IFN receptors. ECP induces bona fide ICD, hence simultaneously providing monocytes with abundant amounts of TAAs and immunostimulatory signals that are sufficient to initiate cognate anticancer immunity.

Due to the radiosensitivity and deep anatomical location of nasopharyngeal carcinoma (NPC), radiotherapy serves as the cornerstone of standardized treatment for this malignancy. Beyond its cytotoxic effects, radiotherapy can serve as an immunological adjuvant by inducing immunogenic cell death (ICD). Dendritic cells (DCs), as potent antigen-presenting cells, play a critical role in tumor immunotherapy, but their exact role in the ICD process of NPC remains unclear. The effects of high-dose radiation (≥2 Gy) on DCs and the type of immune response it elicits in NPC have not been fully elucidated. An study was conducted to assess whether ICD of NPC 5-8F cells induced by high-dose radiation could regulate the immune response of DCs. Specifically, the maturation and antigen-presenting capacity of DCs were evaluated following co-culture with NPC cells exposed to high-dose radiation. High-dose radiation was found to induce ICD in NPC 5-8F cells, as evidenced by increased pro-inflammatory factor levels and reduced anti-inflammatory factor levels in the cell culture supernatant. Co-culture with NPC cells exposed to high-dose radiation for 15 minutes significantly enhanced the expression of surface molecules on DCs, promoting their immune sensitization. High-dose radiation-induced apoptosis of NPC 5-8F cells is a form of ICD, which plays an important role in regulating DC immune function. These findings provide insight into the immunomodulatory effects of radiotherapy in NPC and its potential to enhance tumor immunotherapy through DC activation.

The immune system plays a central role in anticancer defense by coordinating antitumor responses that inhibit the initiation, progression, and metastasis of malignancies. Emerging evidence underscores the crucial interplay between regulated cell death (RCD) pathways and immune activation, particularly immunogenic cell death (ICD). ICD refers to a specific form of regulated cell death in which tumor cells undergo death and release damage-associated molecular patterns (DAMPs) and other signaling molecules, thereby reshaping the tumor immune microenvironment (TIME). While the canonical RCD pathways are well-established, the inducers of ICD, the spatiotemporal regulation of TIME dynamics, and the functional states of immune cells remain incompletely understood. We thoroughly evaluated contemporary therapeutic approaches that exploit the mechanisms of RCD-driven immunomodulatory effects, including strategies to potentiate ICD and amplify antitumor immune responses. The novelty of this review lies in its dual perspective: delineating how tumor-intrinsic death programs reprogram the tumor TIME and how immune-cell death directly dictates its polarization toward immunostimulatory versus immunosuppressive states, ultimately shaping therapeutic outcomes. We analyzed in depth how different forms of RCD shape antigen presentation, guide immune cell infiltration, and affect checkpoint signaling, underscoring their dual potential to support or hinder antitumor responses. Furthermore, we summarized the current landscape of ICD-inducing interventions, including chemotherapy, radiotherapy, oncolytic viruses, tumor vaccines, and nanotechnology-based platforms, underscoring their potential to convert immunologically “cold” tumors into “hot” ones and to synergize with immune checkpoint blockade. In addition, we highlighted promising combination strategies aimed at directly modulating immune cell death pathways to sustain effector cell function and overcome exhaustion, offering novel insights for the development of next-generation precision immunotherapies. By delineating the crosstalk between tumor/immune cell death pathways, this study provides a roadmap for developing precise immunotherapies that exploit RCD-TIME interactions to overcome treatment resistance.

Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated immunogenic cell death (ICD). ICD has demonstrated potential to overcome resistance to conventional cancer therapies, enhancing the efficacy of treatments such as chemotherapy, radiotherapy, immunotherapy and photodynamic therapy. Notably, in the context of radiotherapy, ferroptosis serves a key role, particularly when combined with radioimmunotherapy. Mitochondria are central to the regulation of radiation-induced oxidative stress and the remodeling of the immune microenvironment, and they undergo characteristic morphological changes during the ferroptotic process. However, the precise regulatory association between mitochondrial dysfunction and ferroptosis remains incompletely understood, and there is an ongoing debate regarding this complex interaction. The present review aimed to explore the mechanisms through which mitochondria and ferroptosis interact in the context of radiotherapy, with a focus on how ferroptosis exacerbates mitochondrial dysfunction. Additionally, the present review proposed novel strategies leveraging radioimmunotherapy to offer more precise and effective approaches for cancer treatment.

Immunogenic cell death (ICD) is a programmed pathway leading to cell death and promotion of immunological responses. Melanoma is resistant to chemotherapy and radiotherapy (RT). Disulfiram (DSF), which forms complexes with copper (Cu), has been shown to induce ICD of many tumor types. Here, we aim to investigate whether DSF/Cu combined with irradiation (IR) can induce ICD and exert anti-cancer effects in melanoma. In vitro experiments, treatment of MV3 and B16F10 melanoma cells with DSF/Cu + IR significantly increased the cellular apoptosis and increased ICD markers: damage-associated molecular pattern molecule (DAMP) exposure and release, including calreticulin cell surface expression, high-mobility group box 1 (HMGB1) release, and decreased intracellular ATP levels. In addition, DSF/Cu combined with IR treatment inhibited tumor growth and enhanced tumor-infiltrating immune cells in the B16F10-bearing C57BL/6 model. Our findings reveal that combining IR with DSF/Cu induces ICD and inhibits tumor growth in melanoma, providing a promising strategy to overcome the inherent resistance of RT in melanoma.

Radiotherapy is a commonly used method in the treatment of bladder cancers (BC). Radiation-induced immunogenic cell death (ICD) is related to the immune response against cancers and their prognoses. Even though dendritic cells (DC) act as powerful antigen-presenting cells in the body, their precise role in this ICD process remains unclear. Accordingly, an in vitro study was undertaken to ascertain whether high-dose radiation-induced ICD of BC cells could regulate the immune response of DC. The results indicated that high-dose radiation treatments of BC cells significantly increased their levels of apoptosis, blocked their cell cycle in the G 2 /M phase, increased their expression of ICD-related proteins, and upregulated their secretion of CCL5 and CCL21 which control the directed migration of DC. It was also noted that expression of CD80, CD86, CCR5, and CCR7 on DC was upregulated in the medium containing the irradiated cells. In conclusion, the present findings illustrate that high-dose radiation can induce the occurrence of ICD within BC cells, concomitantly resulting in the activation of DC. Such findings could be of great significance in increasing the understanding how radiotherapy of BC may work to bring about reductions in cell activity and how these processes in turn lead to immunoregulation of the function of DC.

Minibeam Radiation Therapy (MBRT) uses sub-millimetric beams to generate highly heterogeneous dose distributions and has shown promising results in preclinical glioblastoma by preserving normal tissue while eliciting immune responses. However, the initiating molecular mechanisms remain unclear. We hypothesised that immunogenic cell death or cGAS-STING pathway activation could be involved. We evaluated cell death, damage-associated molecular patterns (calreticulin exposure and HMGB1 release), RT1a exposure, and cGAS-STING activation 24 h after irradiation. MBRT was compared with conventional radiation therapy (CRT; X-rays or protons) in glioblastoma cell lines (F98, RG2) and normal astrocytes using flow cytometry and qPCR. CRT induced dose-dependent tumour cell death, whereas MBRT caused lower, non-dose-dependent effects. Astrocytes showed similar responses to both modalities. Immunogenic markers were limited: CRT increased calreticulin and RT1a exposure more than MBRT, while HMGB1 was undetectable. No transcriptional activation of the cGAS-STING pathway was detected, although interferon-stimulated genes were partially upregulated in F98 cells. RG2 cells showed no immune activation. CRT selectively induced Cxcl10 expression in astrocytes. MBRT and CRT induce distinct biological and immune-related responses in tumour cells and astrocytes in vitro, suggesting different tumour-intrinsic mechanisms; whether these translate to broader immunogenic effects in vivo remains to be determined.

Background Carbon ion radiotherapy (CIR) has emerged as a promising therapeutic modality for photon-resistant malignancies due to its unique physical depth-dose distribution and enhanced radiobiological effectiveness. Nevertheless, treatment resistance persists in certain recurrent or refractory head and neck squamous cell carcinoma (HNSCC) cases, underscoring the need for novel combinatorial strategies. Here, we demonstrated the sensitizing effect of targeting discoidin domain receptor 1 (DDR1) in HNSCC for CIR. Methods MOC1 and and Cal27 cell lines along with tumor-bearing C57BL/6 mice were used for in vitro and in vivo studies. DDR1 was knocked down via lentivirus. Cell viability and proliferation were assessed by CCK-8 and colony formation assays. Immunogenicity and tumor-infiltrating lymphocytes were measured via flow cytometry and immunofluorescence. Tumor suppression mechanisms were investigated using RNA sequencing and bioinformatics. Ferroptosis markers (lipid peroxidation, iron, ROS) were detected using MDA, BODIPY 581/591 C11, FerroOrange, and DCFH-DA probes. Upstream ferroptosis mechanisms were analyzed by Western blot, co-immunoprecipitation, key molecule modulator administration, and SCD1 overexpression. Results We demonstrated that targeting DDR1 potentiated CIR by triggering ferroptosis-mediated immunogenic cell death, which in turn enhanced antitumor immunity. Mechanistically, DDR1 sustained tumor cell survival by forming 14–3-3-mediated assembly of a DDR1/14–3-3/Akt ternary complex, thereby activating the Akt/mTORC1/SREBP1/SCD1 axis to promote monounsaturated fatty acid (MUFA) biosynthesis and suppress ferroptosis. Silencing DDR1 disrupted this complex, alleviating MUFA-mediated ferroptosis inhibition and subsequently increasing tumor immunogenicity. This immunogenic shift facilitated CD8 + T cell infiltration and cytotoxicity, amplifying CIR-induced tumor suppression. Furthermore, pharmacological inhibition of DDR1 using the small-molecule inhibitor 7rh recapitulated these effects, demonstrating potent anti-proliferative and ferroptosis-inducing capabilities, enhancing CIR sensitivity to better control tumor progression. Conclusions Our findings positioned DDR1 targeting as a therapeutic strategy to potentiate CIR through immunogenic ferroptosis induction in HNSCC.