Abscopal Effect Research Articles

Microwave ablation combined with α-PD-L1 enhances abscopal effect and promotes CTL activation and intratumoral homing by a cytokine network involving IFN-γ and CXCL9.

Microwave ablation combined with α-PD-L1 enhances abscopal effect and promotes CTL activation and intratumoral homing by a cytokine network involving IFN-γ and CXCL9.

PAI-1-driven SFRP2high cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy.

PAI-1-driven SFRP2high cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy.

Metronomic Photodynamic Therapy With Immune Checkpoint Inhibitors Does Not Affect Nontarget Lesions.

Metronomic Photodynamic Therapy With Immune Checkpoint Inhibitors Does Not Affect Nontarget Lesions.

MXene-based nanosheet for enhanced glioma therapy via photonic hyperthermia to boost the abscopal effect of radioimmunotherapy

Radiotherapy (RT) effectiveness is limited by low DNA damage in tumor cells, surrounding tissue harm, and tumor radioresistance with active DNA repair. Herein, we have engineered a two-dimensional nanomaterial consisting of MXene nanosheets at its core, coated with gold nanorods and a cisplatin shell, and further modified with polyvinyl alcohol, referred to as APMP. The APMP exploits its distinctive electronic properties and photothermal effects to augment radiosensitivity and impede DNA damage repair mechanisms. In vitro experiments demonstrate that APMP elevates reactive oxygen species (ROS) production to approximately 2.6 times higher than that achieved with radiotherapy alone, thereby significantly enhancing the sensitivity to radiotherapy. Combining APMP with photothermal therapy (PTT) and RT is a promising glioblastoma treatment strategy, achieving tumor destruction via localized hyperthermia and overcoming radioresistance. This approach achieves precise tumor targeting, reducing side effects and enhancing therapeutic response in preclinical models. The novel core-shell design enables potent radiotherapy-specific radiosensitizers that drive immunogenic cell death, enhancing glioblastoma combination immunotherapy. This universal strategy heralds a new era in integrating radiotherapy sensitizers with immunotherapy.Graphical

Intratumoral Injection of Cytotoxic Drugs Plus Hapten Elicits Significant Immune Responses in Sentinel Lymph Nodes: Implications for Cancer Immunotherapy.

Studying the sentinel lymph nodes (SLNs) to define the metastasis and the mechanisms of abscopal effect. Using scRNA-seq to investigate the cellular and genomic changes of SLNs before or after treatment of the primar pancreatic carcinoma site by intratumoral injection of cytotoxic chemotherapy drugs plus hapten. A very significant decrease of SLN carcinoma cells, but increased macrophages, monocytes, CD8 T-effector cells, and fibroblasts. At the genomic and functional levels, the above treatment increased the ability of angiogenesis, epithelial mesenchymal transition (EMT), and cancer-associated fibroblast (CAF) signaling. In addition, matricellular proteins were upregulated. Our study demonstrated a marked reduction in carcinoma cells within SLNs following treatment, alongside a notable increase in inflammatory and stromal cells, which suggested a dynamic reorganization of the lymph node microenvironment rather than straightforward tumor growth. The absence of significant enlargement of SLNs, despite the increase in cellular density, may be attributed to the remodeling effects induced by the treatment. The observed upregulation of angiogenic factors, EMT pathways, and CAF signaling highlighted a complex interaction between tumor and immune responses. These findings provided new insights into the abscopal effect, revealing how targeted therapies can modulate lymph node microenvironments to enhance local immune responses and potentially improve systemic antitumor efficacy.

Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients.

Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients.

Exploring the landscape of current in vitro and in vivo models and their relevance for targeted radionuclide theranostics.

Cancer remains a leading cause of mortality globally, driving ongoing research into innovative treatment strategies. Preclinical research forms the base for developing these novel treatments, using both in vitro and in vivo model systems that are, ideally, as clinically representative as possible. Emerging as a promising approach for cancer management, targeted radionuclide theranostics (TRT) uses radiotracers to deliver (cytotoxic) radionuclides specifically to cancer cells. Since the field is relatively new, more advanced preclinical models are not yet regularly applied in TRT research. This narrative review examines the currently applied in vitro, ex vivo and in vivo models for oncological research, discusses if and how these models are now applied for TRT studies, and whether not yet applied models can be of benefit for the field. A selection of different models is discussed, ranging from in vitro two-dimensional (2D) and three-dimensional (3D) cell models, including spheroids, organoids and tissue slice cultures, to in vivo mouse cancer models, such as cellline-derived models, patient-derived xenograft models and humanized models. Each of the models has advantages and limitations for studying human cancer biology, radiopharmaceutical assessment and treatment efficacy. Overall, there is a need to apply more advanced models in TRT research that better address specific TRT phenomena, such as crossfire and abscopal effects, to enhance the clinical relevance and effectiveness of preclinical TRT evaluations.

The oncolytic virus of p53-armed NDV, in combination with GM-CSF and iPD-L1, induces the Immunogenic cell death of melanoma

Melanoma is a malignant tumor that mutates from melanocytes on the skin and mucous membranes. (Long et al., 2023) Cutaneous melanoma is the most dangerous skin cancer, which causes 80% of causalities (Saeed et al., 2024). The treatment of melanoma includes wide excision and radiotherapy, which makes it hard to perform a systematic impact and could produce side effects (Sakunchotpanit et al.,2024). As immunotherapy, oncolytic virus therapy provides a pathway to combine a direct attack of this cancer, leading to a favorable prognosis. However, oncolytic virus therapy is fraught with challenges as the generally immunosuppressive tumor microenvironment interferes with inducing an effective systemic immune response. To overcome the immunosuppression, activate the innate immune response, and cause an abscopal effect in tumor treatment, we propose building on a previously described recombinant Newcastle disease virus (NDV) encoding GM-CSF, MEDI5395. Oncolytic virotherapy induces immunogenic cell death (ICD) and antitumor immune responses, which can cause the abscopal effect simultaneously. It has previously been shown that p53 expression in OVs can induce more severe ICD and enhance T-cell infiltration, leading to reduced tumor growth and long-lasting systemic anti-tumor immune response in preclinical models by secreting adenosine triphosphate (ATP) and high-mobility group box protein B1(HMGB1). In this way, untreated tumor cells are also suppressed. iPD-L1 combined with GM-CSF effectively reduces tumor viability, enhances immune cell infiltration, and upregulates immune-related genes, promoting systemic anti-tumor immunity and improved survival in mouse melanoma models. We hypothesize that NDV encoding p53 and iPD-L1/GM-CSF effectively induce immunogenic cell death, enhance immune cell infiltration, and reduce tumor growth, demonstrating significant therapeutic potential in preclinical models. In conclusion, editing such genes in NDV can potentially enhance melanoma’s treatment efficacy, resulting in systemic anti-tumor responses.

Abstract B015: Local delivery of mRNA lipid nano particles encoding an autoactivated cGAS mutant and membrane-tethered IL-12 enhances local and distal tumor control

Abstract Local cancer treatments are often effective in controlling primary tumor growth. However, the abscopal effect induced by local treatment—critical for treating metastatic tumors—is rarely achieved and particularly challenging in less immunogenic tumors. Here, we report that local administration of lipid nanoparticles (LNPs) containing mRNAs encoding an autoactivated cyclic GMP-AMP (cGAMP) synthase (cGAS) R241E mutant and membrane-tethered IL-12 (IL-12TM) induces potent local and systemic tumor control in multiple non-immunogenic murine models, including B16 and TC-1 tumors. The cGAS R241E mutant but not wild-type cGAS mRNA LNPs spontaneously produce cGAMP in vivo and predominately activate conventional DC1, enhancing innate immune sensing and inhibiting tumor growth in a host STING-dependent manner. IL-12TM mRNA LNPs synergize with cGAS R241E mRNA LNPs to promote local IFN-γ production while minimizing systemic exposure compared to soluble IL-12 mRNA LNPs. Mechanistically, combining cGAS R241E and IL-12TM mRNA LNPs (Combo) enhances dendritic cell activation and stimulates antigen-specific CD8+ T cells within the tumor, facilitating their migration to draining lymph nodes. While the multiple immune cell populations contribute to anti-tumor efficacy against local tumors, CD8+ T cells and intact IFN-γ signaling are responsible for distal tumor control. Additionally, Combo treatment synergizes with PD-L1 checkpoint blockade to further reduce distal tumor burden. Taken together, these findings demonstrate that mRNA LNP-mediated delivery of the autoactivated cGAS mutant and IL-12TM provides a safe and effective strategy for treating both primary and metastatic tumors. Citation Format: Anli Zhang, Zhijian (James) Chen. Local delivery of mRNA lipid nano particles encoding an autoactivated cGAS mutant and membrane-tethered IL-12 enhances local and distal tumor control [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B015.

Abstract B011: Leveraging the tumor immunogenic effects of ferroptosis to rationally design effective immune based therapies

Abstract Effective combination immunotherapy regimens increase the success rate of treating cancer patients than either monotherapy alone. Ferroptosis is a novel form of cell death that has gained popularity in the last decade as a potential tool to be used against cancer progression but has not had much success clinically. Currently, several groups are studying the relevance of ferroptosis in the context of immunotherapy in an attempt to expand its clinical translatability as well as to overcome the lack of response to immunotherapy alone. The field though is divided regarding the nature of the effects of ferroptosis inducers on the immune system. While some reports suggest that ferroptosis inducers are immunosuppressive, others demonstrate the immune promoting effects elicited by ferroptosis, making it hard to effectively design a combination therapy with clinical potential. A possible explanation is the use of different tumor models or different types of ferroptosis inducers across these studies. In order to rigorously interrogate the use ferroptosis in an immunotherapy regimen, we have evaluated the impact of different classes of ferroptosis inducers with various different immune modulators in several pre-clinical cancer models both in vivo and in vitro. Interestingly, we observed that within the same preclinical model of metastatic melanoma, the choice of the immune modulator used can significantly alter the directionality of the effects of ferroptosis on tumor progression. We confirm that treatment with ferroptosis inducers increases the ability of tumor cells to activate T cells in vitro irrespective of the type of inducer. On the other hand, the quality of immune response in vivo, varies with the class of ferroptosis inducer. We subsequently, designed a regimen with a CD40 agonist that boosts the tumor immunogenic impact of ferroptosis and enhances the activation of the adaptive immune system. This regimen reduces the progression of the treated tumor, elicits an abscopal effect and improves the survival of mice as well. While FDA approved immune checkpoint blockade such as anti-PD1 therapy elicits variable responses based on the type of ferroptosis inducer used, our regimen is effective with either class of ferroptosis inducer in both melanoma and colon cancer pre-clinical models. We are also able to abrogate the effect of each class of ferroptosis inducers by using a ferroptosis inhibitor. Thus, our study evaluates for the first time the contribution of ferroptosis to immune based therapies without the confounding effects due to the chemistry of the small molecule used. In conclusion, our data resolves the conflicting reports about the immune effects of ferroptosis and paves the way for evaluating the clinical efficacy of ferroptosis in combination with appropriate immune modulators. Citation Format: Divya Venkatesh, Daniel Thach, Qian Wang, Rachana R Maniyar, Iken Takiyeddine, Mariam M George, Isabell Schulze, Hengrui Liu, Brent R Stockwell, Jedd D Wolchok, Taha Merghoub. Leveraging the tumor immunogenic effects of ferroptosis to rationally design effective immune based therapies [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B011.

Ethanol inhibits the growth and metastasis of hepatocellular carcinoma by inducing immunogenic cell death

BackgroundImmunogenic cell death (ICD) can elicit an adaptive immune response with significant antitumor effects. Percutaneous ethanol injection therapy has been applied as tumor ablation for small hepatocellular carcinoma (HCC). However,...

A Radiation‐Activated and Self‐Cascade Nano‐Immunostimulator Triggers a Potent Abscopal Effect Against Distant Tumors

AbstractRadiotherapy (RT) inhibits local tumors by stimulating reactive oxygen species (ROS) generation, and sometimes suppresses distant tumors known as the abscopal effect. However, the abscopal effect is rarely observed in clinic, due to insufficient tumor‐associate antigens (TAAs) and weak immune stimulation. Here, a radiation‐activated and self‐cascade nano‐immunostimulator (RAIDER) is fabricated to trigger a potent abscopal effect against distant tumors by unleashing cascade‐amplified ROS generation and boosting antigen presentation. After accumulation in tumors, RAIDER undergoes HAase‐triggered deshielding and charge‐reversal, and GE11 enriched liposomal core and CpG are both released. Under following RT, protoporphyrin IX‐induced Cherenkov radiation‐photodynamic therapy (CR‐PDT) elicits ROS generation, leading to disintegration of RAIDER and catalase (CAT) burst release. Meanwhile, by the combination of RT, CR‐PDT, and CAT‐induced O2 supply, self‐cascade ROS generation is achieved to enhance lysis of tumor cells and release of massive TAAs. Subsequently, the co‐stimulation of TAAs and the released CpG activates dendritic cell maturation to boost antigen presentation, resulting in a strong systemic immune response. Combined with RT, RAIDER exhibits a potent abscopal effect, with an average distant tumor growth inhibition of ≈70.3%. Overall, the strategy amplifies antitumor effect of RT from local to systemic, holding a potential against local and distant tumors.

Immunogenic Cell Death: the Key to Unlocking the Potential for Combined Radiation and Immunotherapy.

Immunogenic cell death (ICD) enhances anti-tumor immunity by releasing tumor-associated antigens and activating the anti-tumor immune system response. However, its potential remains understudied in combination therapies. Here, we develop a mathematical model to quantify the role of ICD in optimizing the efficacy of combined radiotherapy (RT) and macrophage-based immunotherapy. Using preclinical murine data targeting the SIRP α -CD47 checkpoint, we show that RT alone induces minimal ICD, whereas disrupting the SIRP α -CD47 axis significantly enhances both phagocytosis and systemic immune activation. Our model predicts an optimal RT dose (6-8 Gy) for maximizing ICD, a dose-dependent abscopal effect, and a hierarchy of treatment efficacy, with SIRP α -knockout macrophages exhibiting the strongest tumoricidal activity. These findings provide a quantitative framework for designing more effective combination therapies, leveraging ICD to enhance immune checkpoint inhibition and radiotherapy synergy.

In Situ Tumor Vaccination Using Lipid Nanoparticles to Deliver Interferon-β mRNA Cargo.

Background: In situ cancer vaccination is a therapeutic approach that involves stimulating the immune system in order to generate a polyclonal, anti-tumor response against an array of tumor neoantigens. Traditionally, in situ vaccination approaches have utilized adenoviral vectors to deliver immune-stimulating genes directly to the tumor microenvironment. Lipid nanoparticle (LNP)-mediated delivery methods offer several advantages over adenoviral delivery approaches, including increased safety, repeated administration potential, and enhanced tumor microenvironment activation. Methods: To explore in situ vaccination using LNPs, we evaluated LNP-mediated delivery of a reporter gene, mCherry, and an immune-stimulating gene, IFNβ, in several in vitro and in vivo models of lung cancer. Results: In vitro experiments demonstrated successful transfection of murine cancer cell lines with LNPs carrying both mCherry and IFN-β mRNA, resulting in high expression levels and IFNβ production. In vivo studies using LLC.ova flank tumors showed that intratumoral injection of IFNβ-mRNA LNPs led to significant IFNβ production within the tumor microenvironment, with minimal systemic exposure. Therapeutic efficacy was evaluated by injecting established LLC.ova flank tumors with IFNβ-mRNA LNPs bi-weekly for two weeks. Treated tumors showed significant growth inhibition compared to controls. Flow cytometric analysis of tumor-infiltrating leukocytes revealed that tumors injected with IFNβ-mRNA LNPs were associated with an increased CD8:CD4 T-cell ratio among lymphocytes, more CD69-expressing CD8 T-cells, and an increased presence of M1 macrophages. Efficacy and an abscopal effect were confirmed in a squamous cell carcinoma model, MOC1. No toxicity was observed. Conclusions: These findings show that intratumoral LNP delivery of immune-stimulating mRNA transcripts, such as IFNβ, can effectively stimulate local anti-tumor immune responses and warrants further investigation as a potential immunotherapeutic approach for cancer.

4-1BB agonist targeted to fibroblast activation protein α synergizes with radiotherapy to treat murine breast tumor models

BackgroundIonizing radiation (IR) is a double-edged sword for immunotherapy as it may have both immunosuppressive and immunostimulatory effects. The biological effects of IR on the tumor microenvironment (TME) are a...

Hypofractionated radiotherapy combined with a PD-1 inhibitor, granulocyte macrophage-colony stimulating factor, and thymosin-α1 in advanced metastatic solid tumors: a multicenter Phase II clinical trial

PurposeThis multicenter Phase II clinical study assessed the efficacy and safety of hypofractionated radiotherapy (HFRT) in combination with a PD-1 inhibitor, granulocyte macrophage-colony stimulating factor (GM-CSF), and thymosin-α1 in patients with heavily treated metastatic solid tumors.MethodsPatients were enrolled between September 2022 and May 2024. HFRT was administered to targeted tumors, and GM-CSF was administered for 14 days from day 1 of radiotherapy. Thymosin-α1 was injected concurrently twice weekly until disease progression. Immunotherapy with camrelizumab was started following HFRT and repeated every 3 weeks. GM-CSF was administered daily for 7 days before each cycle of immunotherapy.ResultsBy June 15, 2024, there were 37 study participants. The median follow-up duration was 5.97 months (range 0.40–20.9). Median progression-free survival was 3.5 months (95% confidence interval 2.73–4.23) in the intention-to-treat population. The objective response rate was 23.08%, and the disease control rate was 65.38%. Overall survival data are not yet mature. Abscopal effects were observed in 6 patients (23.08%); four of whom achieved a partial response. Patients who achieved a partial response were significantly more likely to have an abscopal effect( P = 0.025). The group with a lower baseline neutrophil–lymphocyte ratio had a significantly lower risks of distant metastasis and death( P = 0.024). Seventeen adverse reactions were reported, including six grade 3 or 4 adverse events. There were no grade 5 adverse events.ConclusionIn conclusion, the trends in efficacy observed in our study are promising; however, well-designed protocols are essential to validate these findings.

Insights into CSF-1/CSF-1R signaling: the role of macrophage in radiotherapy.

Macrophage plays an important role in homeostasis and immunity, and dysfunctional macrophage polarization is believed to be associated with the pathogenesis of tissue fibrosis and tumor progression. Colony stimulating factor-1 (CSF-1), a polypeptide chain cytokine, through its receptor (CSF-1R) regulates the differentiation of macrophages. Recently, the promising therapeutic potential of CSF-1/CSF-1R signaling pathway inhibition in cancer treatment is widely used. Furthermore, inhibition of CSF-1/CSF-1R signaling combined with radiotherapy has been extensively studied to reduce immunosuppression and promote abscopal effect. In addition, cumulative evidence demonstrated that M2 phenotype macrophage is dominant in tissue fibrosis and the inhibition of CSF-1/CSF-1R signaling pathway ameliorated pulmonary fibrosis, including radiation-induced lung fibrosis. Herein, we provide a comprehensive review of the CSF-1/CSF-1R signaling pathway in radiotherapy, with a focus on advances in macrophage-targeted strategies in the treatment of cancer and pulmonary fibrosis.

CV1-secreting sCAR-T cells potentiate the abscopal effect of microwave ablation in heterogeneous tumors.

CV1-secreting sCAR-T cells potentiate the abscopal effect of microwave ablation in heterogeneous tumors.

Regression of all untreated lesions in multifocal low-grade meningioma following fractionated stereotactic radiotherapy-abscopal effect or spontaneous regression? : Case report and review of the literature.

Abscopal effects have been reported predominantly in metastatic cancers, indicating aradiographic response in alesion that has not been included in the radiotherapy target volume. The response is interpreted as ahumoral immune response to radiotherapy-generated tumour-specific antigens. In this case study, we present the first histologically confirmed multifocal low-grade meningioma with spontaneous regression of all other lesions after conventionally fractionated stereotactic radiotherapy (RT). Two localisations, right frontal and right spheno-orbital, were resected at the time of the initial diagnosis in a66-year-old woman. RT was performed 1year later to aprogressive occipital lesion at the cerebral falx. Regular magnetic resonance imaging (MRI) showed slightly decreasing tumour volume in untreated lesions 1year after RT and continued during further follow-up. Up to > 7years after treatment, MRI demonstrated an almost complete response of all initial lesions. Two prior reports withmeningioma were published in onepatient with an atypical meningioma after conventionally fractionated RT and anotherpatient with an intracranial meningiomatosis after radiosurgery. This case study supports the concepts of treating only progressive or symptomatic meningioma lesions locally and careful regular MRI surveillance for further assessment. Potential active interventions to trigger an abscopal effect are currently not known. Further research of this beneficial effect for our patients should be supported.

Th1 adjuvant ARNAX, in combination with radiation therapy, enhances tumor regression in mouse tumor-implant models

Th1 adjuvant ARNAX, in combination with radiation therapy, enhances tumor regression in mouse tumor-implant models