Search Results (161)

Radiotherapy (RT) has traditionally been considered a local treatment modality; however, accumulating evidence suggests that it can induce systemic antitumor responses outside the irradiated field. The classical abscopal effect, defined as the regression of non-irradiated tumor lesions following localized RT, has gained renewed attention in the era of immune checkpoint inhibitors (ICIs). Preclinical and clinical studies have demonstrated that RT can promote immunogenic cell death, antigen presentation, cytokine release, and adaptive immune activation, processes that may contribute to systemic antitumor immunity, particularly when combined with ICIs. Clinically apparent abscopal responses remain rare and heterogeneous, and the biological mechanisms underlying these phenomena are not completely understood. Systemic tumor regression has occasionally been observed in clinical settings that do not involve checkpoint blockade, including RT alone, chemotherapy-containing regimens, and central nervous system-directed therapies. These findings suggest that radiation-associated systemic antitumor responses may arise through overlapping immunologic mechanisms involving both innate and adaptive immunity, tumor microenvironment remodeling, and treatment-associated cellular stress. This review summarizes the current clinical evidence and biological mechanisms underlying radiation-associated systemic antitumor responses and discusses emerging concepts extending beyond the conventional RT–immunotherapy paradigm. We further examined unresolved challenges, including treatment heterogeneity, biomarker limitations, pseudoprogression, and difficulties in mechanistic confirmation. Finally, we propose that the broader “beyond-abscopal” framework may serve as a hypothesis-generating conceptual model for investigating systemic tumor responses across diverse treatment contexts while emphasizing the need for cautious interpretation and prospective translational validation. Full article

Background/Objectives: Extramedullary disease (EMD) is an aggressive and treatment-resistant manifestation of multiple myeloma with limited therapeutic options, particularly in heavily pretreated patients. Methods: We conducted a retrospective study to evaluate the efficacy and safety of concurrent immune checkpoint inhibitors (ICIs) and radiation therapy (RT) in patients with EMD treated at Hackensack University Medical Center and John Theurer Cancer Center between January 2016 and May 2025. Patients were included if they had confirmed EMD and received nivolumab or pembrolizumab with concurrent RT. Results: A total of 21 patients were included, representing a high-risk cohort with a median of 6 prior lines of therapy (range 2–13), including 47.6% triple-class refractory and 19.0% penta-refractory disease. The overall response rate (ORR) was 47.6%, with a clinical benefit rate of 57.1%. Despite these responses, median progression-free survival (PFS) and overall survival (OS) were 4 and 12 months, respectively. Notably, two patients achieved complete responses with nivolumab and RT early in their treatment course following cellular therapy and remain disease-free at last follow-up. The combination of ICIs and RT was generally well-tolerated, with manageable immune-related adverse events and no treatment-related deaths. Conclusions: These findings suggest that concurrent ICI and RT may provide a signal of treatment responses in a subset of patients with advanced EMD, although durability remains limited. Further prospective studies are warranted to further define the role of this combination and identify patients most likely to benefit. Full article

Background: Osteosarcoma remains a biologically complex and clinically challenging malignancy, with survival gains plateauing despite decades of multimodal therapy incorporating surgery and cytotoxic chemotherapy. Unlike cancers in which mutation-centric precision oncology has yielded transformative advances, osteosarcoma is characterized by profound structural variation, copy number alteration dominance, and dynamic clonal evolution, limiting the effectiveness of single-target approaches. These realities motivate alternative strategy-level frameworks that better align treatment selection with evolving disease behavior. Methods: This narrative educational review synthesizes contemporary evidence from osteosarcoma biology, radiobiology, and translational oncology to propose a state-based framework for integrating radiotherapy—particularly stereotactic body radiotherapy (SBRT/SABR) and spatially fractionated radiotherapy (SFRT)—into osteosarcoma management and clinical trial design. Rather than relying solely on static anatomic stage, this framework emphasizes clinically actionable, time-varying state variables, including disease burden patterns (localized, oligometastatic, polymetastatic), tempo of progression, prior systemic response, and feasibility of complete local control. Results: Within this context, radiotherapy is presented not only as a local control modality but also as a hypothesis-generating biologic intervention, capable of perturbing tumor vasculature, inflammatory signaling, innate DNA-sensing pathways, and immune/myeloid programs in a dose-, fractionation-, and spatial-distribution-dependent manner. The review critically examines both the potential opportunities (e.g., local eradication, immune modulation) and limitations (e.g., rarity of abscopal responses, risk of unintended systemic signaling) of radiobiotherapy combinations, emphasizing the need for cautious interpretation and prospective validation. Conclusions: Finally, the article outlines practical implications for state-stratified, biomarker-embedded clinical trials, highlighting endpoints beyond conventional response criteria, including circulating tumor DNA dynamics, immune and myeloid signatures, and long-term patterns of disease progression. Overall, this review frames radiobiotherapy as an educational and investigational paradigm intended to support rational hypothesis generation, multidisciplinary decision-making, and learning-oriented trial designs in osteosarcoma, rather than as definitive clinical guidance. Full article

Focused ultrasound (FUS)-mediated therapies have evolved with the advent of modern ultrasound-guided technology and MRI imaging, moving from their initial use as thermal ablation to a multifunctional platform for thermal and non-thermal ablation, immunomodulation, and targeted drug delivery. This narrative review explores the potential, limitations, and challenges of ablative high-intensity focused ultrasound (HIFU) therapies: HIFU thermal ablation and non-thermal ablation, histotripsy, as well as non-ablative low-intensity focused ultrasound (LIFU) applications in the management of hepatobiliary cancers. HIFU and histotripsy are reviewed as alternative or complementary treatment options in liver tumors, as well as their potential as bridging therapy. Histotripsy is addressed as a theranostic tool, not only by combining ablation with real-time ultrasound imaging guidance, but also by integrating it with sonobiopsy. It facilitates a liquid sonobiopsy of the ablated tumor by releasing intact tumor antigens and damage-associated molecular patterns, leading to potential molecular profiling. LIFU-induced targeted drug delivery (sono-chemotherapy), sonodynamic therapy, radiosensitization, immunomodulation of the immunosuppressive tumor microenvironment (sono-immunotherapy), and the potential to enhance the effect of immune checkpoint inhibitors in these malignancies are discussed. Since FUS-assisted procedures exhibit dual actions through therapeutic functionality associated with intra- and post-procedural ultrasound imaging guidance, they could have value as a theranostic tool in hepatobiliary interventional oncology. Although promising, the available clinical evidence for FUS-mediated therapies in hepatobiliary malignancies consists predominantly of early-stage feasibility studies, retrospective observational cohorts, and non-randomized comparative analyses. Further studies focused on standardized protocols, validation through large-scale, multicenter, prospective randomized clinical trials comparing FUS-based therapies with established treatments, and long-term follow-up of oncological efficacy could define their future role in multimodal oncological strategies. Full article

Photobiomodulation (PBM), the therapeutic application of red to near-infrared light, has demonstrated neuroprotective effects in preclinical CNS models, yet clinical translation remains inconsistent. This systematic review synthesises evidence for PBM across CNS applications to identify factors associated with therapeutic response. We searched five databases (MEDLINE, Embase, CENTRAL, Web of Science, Scopus) through January 2025 following PRISMA 2020 guidelines. Included studies employed PBM for CNS conditions with quantified neurological, cognitive, or functional outcomes; evidence quality was assessed using RoB 2, ROBINS-I, SYRCLE, and the GRADE framework. Thirty studies met inclusion criteria: 27 human studies (n ≈ 2244 participants) and 3 animal studies spanning Alzheimer’s disease, Parkinson’s disease, stroke, traumatic brain injury, and other CNS conditions. Dosimetry—particularly irradiance and light source type (laser vs. LED)—appears to be the primary factor associated with efficacy for Alzheimer’s disease (GRADE: Moderate); trans-cranial LED shows promise for Parkinson’s disease (GRADE: Low); trans-cranial 808 nm laser demonstrates no benefit for acute ischaemic stroke (GRADE: High). Systemic abscopal mechanisms may offer additional therapeutic pathways warranting investigation. These findings provide a condition-specific framework for rational PBM protocol development, supporting adequate irradiance via laser or intra-nasal delivery for Alzheimer’s disease, LED-based trans-cranial protocols for Parkinson’s disease, and integration of artificial intelligence for personalised optimisation. Full article

Spontaneous regression of metastatic renal cell carcinoma is a rare and incompletely understood phenomenon. We report the case of a 61-year-old man with biopsy-proven pulmonary metastases from clear cell renal cell carcinoma who experienced durable tumor regression without receiving any systemic therapy. The patient underwent cryoablation of a symptomatic iliac bone metastasis and discontinued methotrexate, previously prescribed for inflammatory polyarthritis. Serial imaging demonstrated initial slow progression followed by significant shrinkage of pulmonary and mediastinal lesions, leading to a sustained partial response according to RECIST 1.1 criteria. No disease progression has been observed after extended follow-up. Two non-mutually exclusive mechanisms may explain this observation: restoration of antitumor immunity following withdrawal of immunosuppressive therapy, and a systemic immune response triggered by local tumor destruction (abscopal effect). Although such events are exceptional, this case highlights the potential interplay between immune modulation and local therapies in renal cell carcinoma. Further investigation is warranted to better understand these mechanisms and their potential therapeutic implications. Full article

Background/Objectives: Pulsed Electric Field (PEF) therapy is a non-thermal ablation technique that induces immunogenic cell death through high-voltage, short-duration electrical pulses. This may enhance antitumor immunity by releasing intact tumor antigens and potentially generating abscopal effects. We report early outcomes in 32 patients with primary lung cancer or lung oligometastases treated with PEF at a community hospital, with a median (IQR) follow-up of 180.5 (158–207) days. Methods: This retrospective study collected demographics, cancer type, treatment response, and outcomes for patients undergoing PEF ablation. Tumor response was assessed using Sum of Longest Dimensions per RECIST 1.1 to classify progressive disease, stable disease, partial response, or complete response. Volumetric changes were additionally analyzed using RECIST 1.1 percentage thresholds applied to change in volume. Results: At initial 3-month follow-up, 26 of 32 patients demonstrated stable disease, partial response, or complete response, suggesting an 81.25% disease control rate/clinical benefit rate among this cohort. Among patients with Stage III–IV disease, 27.6% (8/29) showed radiographic evidence of a possible abscopal response. At 6 months, 24 of 32 patients remained alive and evaluable, with 62.5% (20/32) maintaining stable disease, partial response, or complete response. Conclusions: Despite patients having progressive disease on systemic therapy before PEF, early outcomes post-ablation suggest favorable local control and potential immunologic benefit. Patients with early-stage disease not receiving systemic therapy also showed excellent local response. Patients tolerated therapy very well. Clinical benefit was observed in 81.25% of patients at 3 months and 62.5% at 6 months, with radiographic evidence of possible abscopal responses in 27.6% of advanced-stage patients, supporting further exploration of the immunogenic potential of PEF demonstrated in preclinical and emerging clinical studies. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Our previous study demonstrated that combination therapy with local hyperthermia (HT) and anti-CTLA-4 antibody (C4), an immune checkpoint inhibitor, induced regression of both local and distant tumors. However, tumor microenvironment (TME) changes in local and distant tumors following local HT and C4 remain unclear. Here, we aimed to evaluate TME changes in local and distant tumors induced by local HT + C4 therapy. Methods: Murine TNBC cells were inoculated in both legs of male BALB/cAJcl mice, and only one leg was treated with HT (42.5 °C for 20 min). C4 was administered intraperitoneally every 3 days for a total of 3 doses. For CD4⁺ T cell depletion experiments, anti-CD4 antibody (αCD4) was administered intraperitoneally every 3 days for a total of 12 doses. Tumor-infiltrating immune cells in locally heated tumors and unheated distant tumors were analyzed 9 days after the initial treatment. Furthermore, tumor growth in heated tumors and unheated distant tumors under αCD4 administration was evaluated. Results: HT + C4 therapy increased the proportion of helper T cells and elevated the ratio of cytotoxic T cells plus helper T cells to myeloid-derived suppressor cells in both heated tumors and unheated distant tumors. The HT + C4 + αCD4 group exhibited significantly larger tumor growth, compared with the HT + C4 group in both heated (p < 0.01) and unheated distant tumors (p < 0.01). Conclusions: These results suggest that combination therapy of HT and C4 favorably modulates the TME. CD4⁺ T cell infiltration may contribute to both local and distant antitumor effects. Full article

Background: High-risk neuroblastoma (NB) is a pediatric malignancy associated with metastases and an immunosuppressive tumor microenvironment. Standard-of-care treatments like chemotherapy are often ineffective, which motivates the investigation of adjuvant approaches. Histotripsy is a noninvasive focused ultrasound therapy that ablates tissue through the mechanical action of bubble clouds. In addition to disruption of the targeted tumor, non-targeted lesions may exhibit growth delay after the histotripsy procedure. The primary hypothesis of this study was histotripsy-induced shifts in the tumor microenvironment will improve the response of metastatic NB to chemotherapy. Methods: Female A/J mice flanks were inoculated bilaterally with 1 × 10⁶ Neuro-2a cells. Histotripsy was applied to one tumor (200–500 mm³), with or without concurrent administration of liposomal doxorubicin (LDOX). The contralateral tumor served as a model of non-targeted distal metastases. Following treatment, tumors were monitored indefinitely for growth, or assessed after 5–7 days with flow cytometry, single-cell RNA sequencing, and immunohistochemistry. Results: Histotripsy alone delayed the growth of treated and contralateral tumors relative to controls (p = 0.01 and p < 0.0001, respectively) and increased CD8⁺ T and CD11b⁺ cells (p < 0.05 for both comparisons). Further, NB cells in targeted and contralateral tumors exhibited a decrease in c-Myc expression and cell-cycle activity, and upregulation of interferon and apoptosis pathways. Histotripsy combined with LDOX had the longest delay in tumor growth (p < 0.0001 vs. untreated controls; p < 0.001 vs. other arms) and greatest expression of CD8⁺ and MOMA staining. Conclusions: These findings indicate that histotripsy induces a systemic antitumor immune response that potentiates chemotherapy efficacy in this model of metastatic NB. Full article

Background: The optimal sequencing of radiotherapy and immunotherapy in early-stage breast cancer remains uncertain. Although synergistic interactions between radiotherapy and immunotherapy have been widely reported, most available evidence derives from advanced disease with high tumor burden. Whether treatment sequencing influences outcomes in postoperative adjuvant therapy has not been well defined. Methods: Patients with stage I–III human epidermal growth factor receptor 2 (HER2)-negative breast cancer who underwent surgery followed by both adjuvant radiotherapy and immunotherapy were identified from the National Cancer Database. According to treatment initiation dates, patients were classified into immunotherapy-first and radiotherapy-first groups. Overall survival was compared using Kaplan–Meier analysis and weighted Cox regression. Baseline imbalances were adjusted using inverse probability of treatment weighting. Prespecified subgroup analyses were conducted based on adjuvant chemotherapy status and radiotherapy fractionation regimen. A sensitivity analysis was performed in an independent cohort of stage IV inoperable patients. Results: A total of 3813 patients were included. Immunotherapy-first sequencing was associated with improved overall survival compared with radiotherapy-first sequencing after weighted (HR 0.71; 95% CI 0.56–0.89). The survival benefit was most evident among patients receiving adjuvant chemotherapy (HR 0.63; 95% CI 0.48–0.84), whereas no significant difference was observed in patients without chemotherapy (HR 1.01; 95% CI 0.71–1.44). Subgroup analysis according to radiotherapy fractionation demonstrated a significant advantage of immunotherapy-first sequencing in patients treated with conventional fractionation radiotherapy (HR 0.58; 95% CI 0.36–0.92), but not in those receiving hypofractionated radiotherapy (HR 0.44; 95% CI 0.17–1.13). In stage IV inoperable patients, no survival difference was detected between sequencing strategies (HR 1.04; 95% CI 0.88–1.23). Conclusions: For postoperative patients with low residual tumor burden, particularly those receiving adjuvant chemotherapy, immunotherapy-first strategy may provide stronger synergistic effects and lead to improved survival. In addition, conventional fractionation radiotherapy with lower doses per fraction appears to facilitate more effective interaction with immunotherapy compared with hypofractionated regimens. Prospective trials are needed for further validation. Full article

Metal ions are indispensable for living organisms, participating in essential physiological processes. However, their dysregulated accumulation can trigger cell death and metal overload. The recent discovery of novel regulated cell death modalities, such as cuproptosis and ferroptosis, has significantly advanced the understanding of metal ions in cell fate and immune regulation. This review systematically elucidates the molecular mechanisms underlying metal ion-induced cell death, encompassing oxidative stress, mitochondrial dysfunction, DNA damage, and epigenetic modifications. It further classifies and discusses the hallmarks of various programmed and non-programmed cell death pathways, emphasizing the pivotal role of metal ions in anti-tumor immunity. Moreover, we highlight an emerging therapeutic approach-metal ion-based immunotherapy, which represents a compelling strategy when combined with radiotherapy to amplify therapeutic outcomes. This combined modality holds significant promise for overcoming radiotherapy resistance and expanding its abscopal effects. Finally, current challenges and future research directions in the field of metal immunity are outlined to facilitate the translational application of metal ions in disease therapy and immune modulation. Full article

Hepatocellular carcinoma (HCC) is the sixth most diagnosed cancer worldwide and represents the second cause of cancer-related death worldwide, according to the estimates by Global Cancer Observatory in 2020. Its prognosis is strictly associated with neoplastic stage and liver function. Several treatments are involved in the management of HCC, according to its stage and the patients’ performance status. The abscopal effect is a particular phenomenon taking place in locally advanced or in metastatic cancer, as a positive off-target result of ionizing radiation at a certain distance from the irradiated zone determining a systemic effect due to the increase in tumor immune response, and resulting in the shrinkage of neoplastic lesions with a subsequent increase in tumor prognosis. If future studies will allow one to master its etiological mechanisms and deliberately trigger them, it could represent a notable weapon in the treatment of hepatocellular carcinoma, particularly at advanced stages, in which sometimes it is able to positively modify the patients’ prognosis. The aim of this review is to evaluate the literature available on this intriguing topic and the characteristics of the mechanisms that originate the abscopal effect, the treatments that can elicit this phenomenon, and the possible relevant therapeutic implications. Full article

The limited ability of the immune system to infiltrate solid tumors, attributed to the immunosuppressive tumor microenvironment (TME), remains a significant challenge in cancer therapy oncolytic adenovirus (OAd) that can directly kill tumor cells in addition to inducing both innate and adaptive immune responses. Therefore, the use of OAd to treat tumors is an appealing approach. In this study, we engineered an OAd armed with a human granulocyte–macrophage colony-stimulating factor (GM-CSF), controlled by the E2F promoter, Ad5/3-E2F-d24-GM-CSF (named OAd-Z1). The antitumor activity of OAd was tested in vitro and in vivo. These findings demonstrated that OAd expressed GM-CSF, replicated effectively in tumor cells, inhibited tumor growth, activated the de novo antitumor response, promoted apoptosis and immunogenic cell death in tumor cells, and increased cytokine and chemokine production both in vitro and in vivo. Additionally, OAd demonstrated an abscopal effect and stimulated T lymphocyte infiltration in vivo. Our findings demonstrate that OAd-Z1 represents promising immunotherapeutic candidates for lung cancer, with the potential to enhance systemic antitumor immunity. Full article

Radiotherapy remains a central component of cancer therapy that induces DNA damage and cancer cell death. Beyond its cytotoxic effects, radiotherapy acts as a potent immunomodulator by releasing immunogenic molecules, inflammatory mediators, and neoantigens that shape anti-tumor immunity. Radiation-induced immune responses can have opposing effects, including immune activation or immunosuppression that dictate local tumor responses. Increasing evidence suggests these immunologic effects are not confined to the site of irradiation, as radiation exposure to surrounding normal tissue can trigger systemic immune signaling that affects local tumor progression as well as metastatic spread. This review examines radiotherapy-induced immune responses across three interconnected contexts: (i) tumor-intrinsic signaling during radiation; (ii) tumor microenvironmental changes where innate and adaptive immune responses alter local outcomes; and (iii) systemic and off-target effects contributing to broader immune remodeling. A comprehensive understanding of radiotherapy-induced immune responses will guide therapeutic strategies to enhance its immunological potential while minimizing unintended immune and off-target effects. Full article

Background: The integration of radiotherapy (RT) and immunotherapy (IO) is transforming oncologic paradigms by combining local tumor control with systemic immune activation. In urological cancers—prostate, bladder, and renal cell carcinoma—this strategy is supported by growing biological rationale and promising early clinical results. Methods: This narrative review synthesizes preclinical and clinical evidence on RT–IO combinations in urological malignancies. A comprehensive literature search was performed in PubMed, Embase, and ClinicalTrials.gov, focusing on mechanistic insights, clinical trials, and translational challenges related to RT–IO synergy. Results: Early-phase studies in bladder and renal cell carcinoma demonstrate feasibility, immunogenic enhancement, and manageable toxicity when RT is combined with checkpoint inhibitors. Prostate cancer remains less immunoresponsive but may benefit from RT-induced immune priming, particularly in biomarker-enriched subgroups. Innovations in precision RT, biomarkers, artificial intelligence, and novel immunotherapeutics are shaping future applications. Conclusions: RT–IO combinations represent a promising yet complex frontier in urological oncology. Future success will rely on precision-guided patient selection, optimized trial design, and equitable global implementation to ensure durable clinical benefit. Full article