Efficacy Of Radiotherapy Research Articles

PI3K/AKT/mTOR Targeting in Colorectal Cancer Radiotherapy: A Systematic Review.

Radioresistance is a major challenge in the treatment of patients with colorectal cancer (CRC) and impairs the efficacy of radiotherapy. The PI3K/AKT/mTOR signaling pathway plays a critical role in CRC and contributes to the development of radioresistance. Accordingly, targeting this signaling pathway may be a promising strategy to improve oncotherapy. We performed a systematic search of Scopus, PubMed, Web of Science, Embase, and Medline databases. We included articles that investigated the effects of PI3K/AKT/mTOR pathway inhibitors on improving the efficacy of radiotherapy. Of the 32 articles included in our review, 27 were preclinical studies and 5 were clinical trials. We examined the effects of various signaling pathway inhibitors in combination with radiotherapy. While the efficacy of these therapies when used alone is limited, their combination is associated with reduced survival, induction of apoptosis, and cell cycle arrest, which may increase radiosensitivity. Despite the limited number of studies, this combination therapy has shown favorable treatment outcomes in patients with CRC. PI3K/AKT/mTOR is a critical signaling pathway for cancer cell survival. By inhibiting this pathway, we can increase the efficacy of radiotherapy. These results provide valuable insights for the further development of research and clinical practice in the treatment of colorectal cancer.

Efficacy of radiotherapy in treating local recurrence concomitant with distant metastasis of nasopharyngeal carcinoma: a long-term retrospective multicenter study.

Patients with nasopharyngeal carcinoma (NPC) experiencing locoregional recurrence concomitant with distant metastases (rmNPC) after initial treatment represent a unique subgroup with significant management challenges. This study aimed to evaluate overall survival (OS) in rmNPC patients treated with systemic therapies with or without radiotherapy. This retrospective multicenter study included patients with locally recurrent and metastatic NPC from five hospitals. Kaplan-Meier analyses and log-rank tests were applied to assess survival outcomes based on recurrence and metastasis profiles, as well as treatment modalities. Independent prognostic factors affecting OS were identified using Cox regression models. A total of 52 patients were analyzed, with a median follow-up duration of 68.3 months (range: 7-240 months). The median OS was 23.4 months (range: 11.1-35.6 months), and the 1-, 2-, 3-, 4-, and 5-year OS rates were 61.3%, 46.5%, 31.0%, 27.9%, and 10.5%, respectively. The treatment modality did not significantly affect OS overall (P = 0.071). Median OS was 10.8 months (95% CI, 7.7-13.9) for chemotherapy alone, 24.2 months (95% CI, 8.9-39.4) for chemotherapy combined with PD-1 inhibitors, and 47.1 months (95% CI, 10.2-84.0) for chemotherapy combined with radiotherapy. In patients with oligometastasis, radiotherapy significantly improved OS (50.1 vs. 24.1 months, P = 0.021), whereas no significant OS benefit was observed for radiotherapy in polymetastatic patients (8.6 vs. 14.8 months, P = 0.168). Similarly, radiotherapy extended OS in patients with one-organ metastases (50.1 vs. 24.1 months, P = 0.026), while no significant benefit was observed in those with multiple-organ metastases (8.6 vs. 11.0 months, P = 0.831). Radiotherapy, when combined with other treatment modalities, significantly improves OS in rmNPC patients with oligometastases or one-organ metastases.

Prognostic analysis of helical tomotherapy stereotactic body radiotherapy in multiple primary or second primary lung cancers

PurposeTo evaluate the safety and efficacy of Helical Tomotherapy stereotactic body radiotherapy (HT-SBRT) in treating multiple primary lung cancers (MPLCs) and second primary lung cancer (SPLC).MethodsFrom January 2010 to September 2023, 106 MPLCs and SPLC (T1-3N0M0) underwent HT-SBRT. The cumulative incidence for local recurrence (LR) was calculated using the competing risk approach and compared using Gray’s test. Cancer-specific survival (CSS) and progression-free survival (PFS) were assessed using Kaplan-Meier analysis and log-rank tests.ResultsAfter adjusting for competing risks, the LR rates for all lesions (n = 150) was 15.3%, with 2- and 4-year rates of 7.5% and 11.4%. For second primary lung nodules post-surgery, the cumulative incidence of LR was 16.1%, with 2- and 4-year rates of 6.9% and 8.7%. In MPLCs treated with HT-SBRT, the cumulative incidence of LR was 14.3%, with 2- and 4-year rates of 8.2% and 14.3%. In patients with MPLCs treated with HT-SBRT (n = 27), the CSS rates at 2, 4, and 10 years were 90.5%, 78.6%, and 53.6%, respectively, and the PFS rates were 59.5%, 32.8%, and 24.6%. In patients with SPLC who received HT-SBRT after surgery (n = 79), the CSS rates at 2, 4, and 10 years were 90.9%, 81.7%, and 61.0%, respectively, while the PFS rates were 75.4%, 64.4%, and 58.5%. Additionally, 0.9% of patients experienced grade 3 acute radiation pneumonitis, and no severe (grade 4–5) toxicities were reported.ConclusionsHT-SBRT may be a safe and effective treatment for MPLCs and SPLC, though prospective studies are needed to confirm its efficacy.

Molecular Mechanism and Research Progress of Sphingolipid Metabolism in Regulating Radiation-induced Apoptosis Using Pan-cancer Analysis.

Radiotherapy stands as a cornerstone in cancer therapy, with nuclear DNA acknowledged as the principal target molecule for radiation-induced cellular demise or injury. Nonetheless, an expanding body of contemporary research elucidates the significant contri-bution of sphingolipids to radiation-induced cell death, particularly in modulating radiation-induced apoptosis. Radiation can instigate apoptosis through multiple pathways of sphin-golipid metabolism, encompassing the activation of ceramide synthase, acid sphingomyelin-ase, neutral sphingomyelinase, sphingosine-1-phosphate lyase, and sphingosine-1-phosphate phosphatase, and the inhibition of sphingosine kinase-1. The disruption of sphingolipid me-tabolism leads to an increase in pro-apoptotic sphingolipid ceramide and sphingosine and a decrease in anti-apoptotic sphingolipid sphingosine-1-phosphate, which ultimately triggers apoptosis in tumor cells. The diminished or absent response of sphingolipids to radiation rep-resents one of the contributors to radioresistance. In this context, numerous interventions tar-geting sphingolipids have been utilized to augment radiosensitivity in tumor tissue and miti-gate radiation-induced damage in normal tissue, demonstrating efficacy both in vitro and in vivo. Sphingolipids have also emerged as promising biomarkers for evaluating the response to radiotherapy in patients. Attaining a comprehensive understanding of sphingolipid metab-olism in radiation-induced apoptosis holds the potential to offer an effective strategy for en-hancing the efficacy of radiotherapy and mitigating resistance to such treatment.

Efficacy of Neoadjuvant Short-Course Radiation Therapy Followed by Oxaliplatin-Based Chemotherapy for Locally Advanced Rectal Adenocarcinoma: A Single-Center Experience From Saudi Arabia

Efficacy of Neoadjuvant Short-Course Radiation Therapy Followed by Oxaliplatin-Based Chemotherapy for Locally Advanced Rectal Adenocarcinoma: A Single-Center Experience From Saudi Arabia

Long Non-Coding RNAs in Malignant Human Brain Tumors: Driving Forces Behind Progression and Therapy.

Long non-coding RNAs (lncRNAs) play a pivotal role in regulating gene expression and are critically involved in the progression of malignant brain tumors, including glioblastoma, medulloblastoma, and meningioma. These lncRNAs interact with microRNAs (miRNAs), proteins, and DNA, influencing key processes such as cell proliferation, migration, and invasion. This review highlights the multifaceted impact of lncRNA dysregulation on tumor progression and underscores their potential as therapeutic targets to enhance the efficacy of chemotherapy, radiotherapy, and immunotherapy. The insights provided offer new directions for advancing basic research and clinical applications in malignant brain tumors.

Efficacy of Neoadjuvant Radiotherapy After Chemotherapy and the Optimal Interval from Radiotherapy to Surgery for Borderline Resectable and Resectable Pancreatic Cancer.

Benefits of neoadjuvant treatment for pancreatic cancer with major vessel invasion has been demonstrated through randomized controlled trials; however, the optimal neoadjuvant treatment strategy remains controversial, especially for radiotherapy. Therefore, we aimed to evaluate the efficacy and safety of neoadjuvant radiotherapy followed by chemotherapy and the optimal time interval to undergo surgery after radiotherapy in (borderline) resectable pancreatic cancer. Between 2013 and 2022, patients with (borderline) resectable pancreatic cancer with vessel contact who received 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan or gemcitabine and nanoparticle albumin-bound paclitaxel as initial treatment following surgery were included. Patients who received radiotherapy after chemotherapy and those who did not were matched using 1:1 nearest-neighbor propensity scores. Propensity scores were measured using the tumor size at initial image, duration of neoadjuvant chemotherapy, and responsiveness to neoadjuvant chemotherapy. Of 212 patients, 166 patients were retrieved for the matched cohort. Patients who received radiotherapy had significantly better postoperative survival, local control, and R0 resection rates than those who did not. Furthermore, patients who underwent surgery within 4 weeks after completing radiotherapy had lower intraoperative blood loss and a clinically relevant postoperative pancreatic fistula rate than those who underwent surgery after more than 4 weeks. In patients with (borderline) resectable pancreatic cancer with vessel contact who were scheduled for curative-intent surgery after neoadjuvant chemotherapy, additional radiotherapy was associated with better postoperative survival and local control. Furthermore, our findings suggested that scheduling surgery within 4 weeks following radiation therapy might enhance the perioperative outcomes.

Radiotherapy combined with chemoimmunotherapy improves survival compared to chemoimmunotherapy alone as first-line treatment for oligometastatic esophageal squamous cell carcinoma.

To evaluate the safety and efficacy of radiotherapy combined with chemoimmunotherapy (RCIT) versus chemoimmunotherapy (CIT) alone as first-line treatment for oligometastatic esophageal squamous cell carcinoma (OESCC) at initial diagnosis. We retrospectively evaluated 140 patients newly diagnosed with OESCC who received RCIT or CIT as first-line treatment between June 2018 and December 2021. Among them, 76patients were in the RCIT cohort and 64patients in the CIT cohort. Propensity score matching (PSM) was used to simulate random allocation. After 1:1 PSM, 61well-paired patients were selected. The median follow-up duration was 34.7 months (95%CI: 30.6-38.8 months). After PSM, the median PFS for the RCIT and CIT groups was 10.9 (95%CI: 9.4-12.4) months and 7.3(95%CI: 6.0-8.7) months, respectively (P = 0.004). The median OS for the RCIT and CIT groups was 22.4 (95%CI: 17.5-27.4) months and 13.4 (95%CI: 10.9-15.9) months, respectively (P = 0.031). There were significant differences in PFS (median PFS: 12.9 vs.8.6 vs.7.3months, P = 0.003) between the group receiving radiotherapy (RT) for all lesions, the group receiving RT for partial lesions, and the CIT group, while OS was on the threshold of significance (median OS: 29.4 vs. 17.3 vs. 13.4 months, P = 0.052). No significant differences in the incidence of grade3 or higher (G3+) treatment-related adverse events (TRAEs) were observed between the two groups. However, the incidence of G3+ pneumonitis (13.1% vs 1.6%, P = 0.038) were higher in the RCIT group compared to the CIT group. RCIT as first-line treatment for OESCC was safe and efficacious. RCIT improved PFS/OS compared to CIT without increasing the overall high grade toxicity rate. However, the increased incidence of pneumonitis due to RT implementation cannot be disregarded.

Efficacy and safety of robotic Cyberknife radiotherapy in uveal melanoma: a systematic review and meta-analysis.

This systematic review is aimed to evaluate the efficacy and safety of robotic Cyberknife radiotherapy (CKRT) in the treatment of uveal melanoma (UM). Clinical studies published in English that assessed the efficacy and safety of robotic CKRT in UM were systematically searched in PubMed, Web of Science, Cochrane and Embase from inception to July 2023. Studies reporting extraocular tumours or other radiosurgery approaches were excluded. Outcomes measured were tumour size, reflectivity, local tumour control rate, eye retention rate, survival rate, complication rate, recurrence rate, and metastasis rate. Ten eligible articles involving 2370 patients with 2372 UMs were included in evidence synthesis. Meta-analysis showed 811 of 912 patients (0.89, 95% Cl: 0.86, 0.92) maintained local control for three years, and 1448 of 1724 patients (0.84, 95% Cl: 0.81, 0.88) preserved the eye in three years. During follow-up, 91% (0.91, 95% Cl: 0.85, 0.97) patients survived and 351 of 1720 patients (0.23, 95% Cl: 0.09, 0.37) involving 1722 eyes had tumour recurrence. In addition, 1376 patients (0.79, 95% Cl: 0.77, 0.82) preserved the eyeball in five years. Following treatment, approximately 20% of patients had radiation retinopathy (95% Cl: 0.13, 0.28), 19% developed glaucoma (95% Cl: 0.11, 0.28), and 22% experienced retinal detachment (95% Cl: 0.07, 0.36). CKRT is a viable, noninvasive RT for UM. The rate of local tumour control following treatment is comparable to that of other RT approaches, providing additional options based on the patient's condition.

NVP-AUY922 relieves radiation-induced intestinal injury via regulating EPHX1.

As a common side effect of radiotherapy, radiation-induced intestinal injury (RIII) greatly affects the prognosis of patients and the efficacy of radiotherapy. Current therapeutic strategies for RIII are still very limited. Thus, the identification of effective radioprotective agents is of great importance. NVP-AUY922 is an HSP90 inhibitor with favorable anti-inflammatory and antioxidant activities. It has been proven to mitigate radiation-induced lung injury. However, its effects on the alleviation of RIII remain unclear. In this study, our data indicated that NVP-AUY922 remarkably increased the survival rate after radiation exposure. NVP-AUY922 treatment could enhance the viability of intestinal stem cells (ISCs) and promote the recovery of the small intestine. In addition, it also inhibited intestinal inflammation and reshaped the gut microbiota structure. We found that the radioprotective effect of NVP-AUY922 is partially dependent on EPHX1. In addition, NVP-AUY922 could attenuate dextran sulfate sodium (DSS)-induced colitis and promote intestinal barrier recovery. Thus, our results suggest that NVP-AUY922 contributes to the amelioration of intestinal injury after radiation exposure, which offers a new approach for the prevention of RIII.

Enhancing Radiation Therapy Response in Prostate Cancer Through Metabolic Modulation by Mito-Lonidamine: A 1H and 31P Magnetic Resonance Spectroscopy Study.

Radiation therapy (RT) is the cornerstone treatment for prostate cancer; however, it frequently induces gastrointestinal and genitourinary toxicities that substantially diminish the patients' quality of life. While many individuals experience transient side effects, a subset endures persistent, long-term complications. A promising strategy to mitigate these toxicities involves enhancing tumor radiosensitivity, potentially allowing for lower radiation doses. In this context, mito-lonidamine (Mito-LND), an antineoplastic agent targeting the mitochondrial electron transport chain's complexes I and II, emerges as a potential radiosensitizer. This study investigated Mito-LND's capacity to augment RT efficacy and reduce adverse effects through comprehensive in vitro and in vivo assessments using hormone-sensitive and hormone-refractory prostate cancer models. Employing a Seahorse analysis and 1H/31P magnetic resonance spectroscopy (MRS), we observed that Mito-LND selectively suppressed lactate production, decreased intracellular pH, and reduced bioenergetics and oxygen consumption levels within tumor cells. These findings suggest that Mito-LND remodels the tumor microenvironment by inducing acidification, metabolic de-energization, and enhanced oxygenation, thereby sensitizing tumors to RT. Our results underscore the potential of Mito-LND as a therapeutic adjunct in RT to improve patient outcomes and reduce radiation-associated toxicities in early-stage prostate cancer.

Targeting autophagy to enhance chemotherapy and immunotherapy in oral cancer.

Oral cancer is a highly malignant disease characterized by recurrence, metastasis, and poor prognosis. Autophagy, a catabolic process induced under stress conditions, has been shown to play a dual role in oral cancer development and therapy. Recent studies have identified that autophagy activation in oral epithelial cells suppresses cancer cell survival by inhibiting key pathways such as the mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK), while activating the adenosine monophosphate-activated protein kinase (AMPK) pathway. Inducing autophagy promotes degradation of eukaryotic initiation factor 4E, thus reducing metastasis and enhancing the efficacy of chemotherapy, radiotherapy, and immunotherapy. Furthermore, autophagy induction can modulate the tumor immune microenvironment and enhance antitumor immunity. This review comprehensively summarizes the relationship between autophagy and oral cancer, focusing on its mechanisms and therapeutic potential when combined with conventional treatments. While promising, the precise mechanisms and clinical applications of autophagy inducers in oral cancer therapy remain to be elucidated, offering new directions for future research to improve treatment outcomes and reduce recurrence.

Combined treatment of small cell lung cancer using radiotherapy and immunotherapy: Challenges and updates.

Currently, chemotherapy remains the standard first- and second-line treatment for small cell lung cancer (SCLC). Research concerning immunotherapy has brought about a remarkable development in the treatment pattern of SCLC. Atirizumab, duvalizumab, atezolizumab, and serplulimab can significantly improve the clinical outcomes of SCLC. Given the rapidly evolving concept that combining immunotherapy with radiotherapy can increase therapeutic effectiveness, clinicians are devoted to further improving local tumor control by integrating immunotherapy with radiotherapy. This paper reviews the research progress in this field to date and explores ways to further enhance the efficacy of this combination therapy. We first discussed that immunotherapy combined with radiotherapy can improve the abscopal effect, progression-free survival, and overall survival rates of SCLC patients. Then, the biomarkers related to the radiation immune microenvironment, such as programmed death ligand-1 (PD-L1), tumor mutational burden (TMB), and the immune function of patients were discussed. Next, we explored the occurrence and underlying mechanisms of immune resistance during radiotherapy implementation. Finally, we clarified that the emerging trend of low-dose radiotherapy help overcome the inhibitory signals that limit T-cell infiltration in the tumor matrix. In summary, considering the rapid development of this field, these combined therapy strategies may have unlimited potential to further improve the efficacy of radiotherapy combined with immunotherapy for patients.

Advances in nanoparticle-based radiotherapy for cancer treatment.

Radiotherapy has long been recognized as an effective conventional approach in both clinical and scientific research, primarily through mechanisms involving DNA destruction or the generation of reactive oxygen species to target tumors. However, significant challenges persist, including the unavoidable damage to normal tissues and the development of radiation resistance. As a result, nanotechnology-based radiotherapy has garnered considerable attention for its potential to enhance precision in irradiation, improve radiosensitization, and achieve therapeutic advancements. Importantly, radiotherapy alone frequently falls short of fully eradicating tumors. Consequently, to augment the efficacy of radiotherapy, it is often integrated with other therapeutic strategies. This review elucidates the mechanisms of radiotherapy sensitization based on diverse nanoparticles. Typically, radiotherapy is sensitized through augmenting reactive oxygen species production, targeted radiotherapy, hypoxia relief, enhancement of antitumor immune microenvironment, and G2/M cell cycle arrest. Moreover, the incorporation of nanoparticle-based anti-tumor strategies with radiotherapy markedly enhances the current state of radiotherapy. Additionally, a compilation of clinical trials utilizing nano-radioenhancers is presented. Finally, future prospects for clinical translation in this field are thoroughly examined.

X-ray induced in-situ ferroptosis through the Fenton reaction of iron supplements for the cancer therapy

The potential of iron-based therapeutic agents in enhancing radiotherapy efficacy through catalyzing the Fenton reaction has garnered widespread interest. The inherent instability of ferrous ions requires the use of complex ligands for the ligand-dependent reduction from Fe3+ to Fe2+, thereby boosting ferroptosis through inducing the Fenton reaction. However, the reliance on complex redox systems and potential long-term toxicity have seriously limited the clinical application in cancer treatment. In this study, we propose an innovative approach that utilizes the reduction capabilities of hydrated electrons generated by X-ray to directly reduce both ferric ions (Fe3+) and Iron Proteinsuccinylate, a clinically used iron supplement. Our experiments showed that over 20 % of Fe3+, at a concentration of 23 μM, was reduced by X-ray without the need for ligand involvement. Furthermore, both in vitro and in vivo studies confirmed that Iron Proteinsuccinylate exhibited the highest tumor growth inhibition rate through the Fenton reaction and ferroptosis, offering a new and safer method for the in-situ reduction of Fe3+ and enhancing the efficacy of radiotherapy.

Indium(iii) complexes with Schiff base-derived polydentate ligands: chemotherapeutic, radiochemotherapeutic, and radiosensitizer potentials against breast tumor cells

In(iii) and 114mIn(iii) complexes with polydentate Schiff base-derived ligands showed cytotoxic activity against MCF-7 and MDA-MB-231 breast tumor cells. The In(iii) complexes presented radiosensitizer effects, improving the efficacy of radiotherapy.

Technological Advances in Radiation Oncology

Abstract One of the most technologically advanced treatment modalities for cancer is radiotherapy (RT). Because of advancements in computer and engineering over the past few decades, RT approaches have undergone significant modification. Our goal is to draw attention to the latest advancements in radiation oncology, with an emphasis on both biological and technological innovations. Modern treatment methods using photon beams, including intensity-modulated radiotherapy, volumetric-modulated arc therapy, stereotactic body radiotherapy, and adaptive radiotherapy, will be demonstrated. A highly customized dosage distribution with the greatest amount of normal tissue preservation is feasible. Imaging, defining the tumor and the organs at risk, treatment planning, and, lastly, image-guidance for precise tumor localization both before and during treatment delivery will all be examined. The critical function that imaging plays throughout the entire process will receive special attention. In the case of adaptive radiotherapy, multimodality imaging that combines morphological, functional, and metabolic data is primarily responsible for the accurate identification of target volumes and the tracking of tumor response or change over the course of treatment. Furthermore, breathing adaptive approaches that correct for tumor movements caused by respiration require real-time imaging of the tumor. The recent popularity of particle beam therapy—specifically, the use of protons—as well as the relatively new experience with heavy particles like carbon ions will be briefly discussed. Lastly, we’ll examine the most recent biological developments in tumor targeting. In fact, the integration of radiobiological information to create more effective and individualized treatment plans has increased the efficacy of RT in addition to technological advancements.

Evaluating the efficacy of preoperative radiotherapy in breast cancer patients non-responsive to neoadjuvant chemotherapy: A clinical trial

Evaluating the efficacy of preoperative radiotherapy in breast cancer patients non-responsive to neoadjuvant chemotherapy: A clinical trial

GPR37-enhanced ubiquitination of ATP1A1 inhibits tumor progression and radiation resistance in esophageal squamous cell carcinoma

Radiotherapy resistance is one of the main reasons for the dismal clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). Therefore, clarifying the targets and molecular mechanisms of radiotherapy resistance in ESCC is of great theoretical and clinical significance to enhance the efficacy of radiotherapy. In this study, GPR37 was identified as a key factor facilitating ESCC radiosensitization. We found that GPR37 is lowly expressed in ESCC, especially in radioresistant ESCC tumors. And its insufficiency is related to the malignant characteristics and unfavorable prognosis in ESCC. Further investigation revealed that GPR37 level is inversely regulated by promoter methylation but positively regulated by ZNF750. Functionally, GPR37 could not only overcome radioresistance of ESCC, but also inhibit proliferation, migration, and invasion. Mechanistically, GPR37 interacts with the ATP1A1 protein, effectively promoting its ubiquitination-induced degradation, thereby limiting the activation of the AKT/mTOR signaling pathway. Additionally, GPR37 can be transported to recipient cells via exosomes and inhibit the malignant behavior of recipient cells. Overall, these findings suggest that GPR37-ATP1A1 axis holds potential as a therapeutic target for the management of ESCC, especially for overcoming radiation resistance.

Concurrent Amplification of Ferroptosis and Immune System Activation Via Nanomedicine-Mediated Radiosensitization for Triple-Negative Breast Cancer Therapy.

Radiation therapy (RT) is one of the core therapies for current cancer management. However, the emergence of radioresistance has become a major cause of radiotherapy failure and disease progression. Therefore, overcoming radioresistance to achieve highly effective treatment for refractory tumors is significant yet challenging. Here, pH-responsive DSPE-PEoz modified hollow Bi2Se3-RSL3/diABZi (DP-HBN/RA) nanomedicine is designed as a radiation sensitizer for efficient treatment of triple-negative breast cancer by simultaneously amplifying ferroptosis and immune system activation. DP-HBN/RA can efficiently concentrate X-ray radiation energy inside the tumor, thereby promoting precise ionizing radiation exposure in tumor cells to produce large amounts of reactive oxygen species (ROS), leading to lipid peroxidation-induced ferroptosis. Meanwhile, ferroptotic cell death is intensified through the inactivation of GPX4 by RSL3 released from DP-HBN/RA to acidic conditions in the tumor microenvironment. Additionally, DP-HBN/RA enhances RT efficacy to exacerbate unrepairable DNA damage and release DNA fragments that activate the cGAS-STING signal pathway, evoking a systematic immune response. Ingeniously, the released diABZi reinforces cGAS-STING activation to boost the immunology antitumor effect. This work links the induction of ferroptosis and the initiation of systematic immune response to achieve highly effective tumor suppression, which opens up new avenues for future treatments of refractory tumors.