With the advent of the immunotherapy era, the combination of radiotherapy and immunotherapy has become a critical strategy to enhance patient outcomes. In addition to its direct cytotoxicity, radiotherapy modulates the immune response within the tumor and its surrounding microenvironment by stimulating the body’s anti-tumor immune response. This interplay provides the rationale for combining radiotherapy with immunotherapy. This review will summarize the immunomodulatory mechanisms of radiation therapy, evaluate the clinical efficacy and safety of combining radiotherapy with immunotherapy, and outline its current applications, challenges, and future potential. In the future, the combination of radiotherapy and immunotherapy holds immense potential in esophageal cancer treatment. Through additional prospective clinical trials exploring optimal combinations, timing, and biomarkers, we can further refine treatment strategies and enhance patient survival.

Programmed cell death ligand 1 (PD-L1) plays a pivotal role in breast cancer immune evasion, yet tissue-based detection suffers from invasiveness and spatial heterogeneity. This study investigated circulating soluble PD-L1 (sPD-L1) as a non-invasive alternative for tumor microenvironment (TME) assessment and breast cancer diagnosis. Serum sPD-L1 levels were evaluated in healthy and breast-affected populations, with correlations assessed against inflammatory markers and clinicopathological parameters. Diagnostic performance of sPD-L1 was compared to conventional biomarkers using receiver operating characteristic (ROC) curve analysis. Cellular-level interactions were investigated by quantifying sPD-L1 and interleukin-6 (IL-6) in culture supernatants. Circulating sPD-L1 expression was significantly elevated in breast cancer versus healthy controls and benign cases, with notably higher levels observed in advanced stages and distant-metastatic cases. Moderate correlations were observed between serum sPD-L1 and various inflammatory indicators. Specifically, ROC curve analysis identified an optimal diagnostic cut-off value of 1.144 ng/mL for sPD-L1, with its discriminative power outperforming conventional biomarkers such as CEA and CA15-3. In vitro, peripheral blood mononuclear cells (PBMCs) co-cultured with breast cancer cells showed enhanced sPD-L1 and IL-6 secretion versus normal epithelial cell co-cultures, with parallel sPD-L1/IL-6 elevation. This coordinated induction was clinically validated by a positive serum sPD-L1/IL-6 correlation. In conclusion, circulating sPD-L1 represents a promising non-invasive biomarker reflecting TME and disease progression, supporting its potential utility for breast cancer diagnostic discrimination.

Background: Lung adenocarcinoma (LUAD) remains a major clinical challenge in assessment of clinical outcomes and therapeutic response. Although tumor-associated macrophages (TAMs) are known as crucial regulators of tumor progression, their heterogeneity and prognostic relevance in LUAD have not been fully elucidated. Methods: The heterogeneity of TAMs was detected by integration analyses of single-cell data and spatial transcriptome data. The CTSB+ TAM-related signature (CTRS) was developed by machine learning algorithms across four LUAD datasets. Multi-omics analysis and functional experiments were applied to uncover the potential role and mechanism of CTSB+ TAMs in LUAD. Results: Single-cell analysis identified CTSB⁺ TAM as a crucial player in LUAD progression with poor prognosis. The spatial co-localization of CTSB⁺ TAMs and tumor cells was confirmed on LUAD slides. Our proposed CTRS was generated and validated in four independent LUAD cohorts, with high scores indicating unfavorable outcomes Furthermore, high CTRS scores were correlated with immunosuppressive status, and poor responses to immune checkpoint blockade. Functional experiments demonstrated the role of CTSB+ TAMs in boosting proliferation and migration in LUAD cells. Conclusion: Our research develops CTRS with reliable performance in evaluating patient clinical outcomes in LUAD, highlighting its potential utility in clinical decision-making.

Radiotherapy is a fundamental step in the combined treatment of glioblastoma (GBM), while radioresistance of GBM causes limitation of therapeutic efficacy. Natural killer (NK) cells, a potential target of immunotherapy, have attracted considerable attention due to the robust cancer cell-targeted cytotoxicity in combined treatment with radiotherapy, suggesting NK cell regulation might be a radiosensitization strategy. Here we show that a cytotoxic subset of NK cells could be stimulated by ionizing radiation (IR) and accumulate in the GBM tumor microenvironment (TME). Co-culturing with NK cells significantly enhances the GBM cell response to IR, and pharmaceutically depleting NK cells in mice elevates IR-induced tumor growth delay. Specifically, GZMB should be the radiosensitization effector secreted by NK cells. Suppressing GZMB activity remarkably impairs NK-mediated GBM radiosensitization. Meanwhile, administrating exogenous GZMB improves irradiation dose-survival response in vitro or in a xenograft model. Mechanically, GZMB blocks autophagosome-lysosome fusion in GBM cells by directly recognizing and cleaving SDC1, a key regulator of autophagosome maturation, at the valine 225 and aspartate 228 sites. Uncleavable mutation of SDC1 reverses GZMB-mediated radiosensitization in GBM. Further studies demonstrate that cleavage of SDC1 obstructs the localization of TGM2, a key MAP1LC3/LC3 recognizer, on the lysosome surface. Clinical data reveal GBM patients with an SDC1 valine 225 or aspartate 228 mutation display lower response to radiotherapy. In this study, we disclose the critical role of NK cells in tumor radiotherapy through secreting GZMB and impeding autophagosome maturation, as well as propose a potential strategy combining radiotherapy and NK-based immunotherapy against radioresistant GBM.Abbreviations: DEGs: differentially expressed genes; GBM: glioblastoma; GZMB: granzyme B; IL: interleukin; IR: ionizing radiation; IRS: immunoreactive score; LAMP: lysosomal associated membrane protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; mSDC1: mutant SDC1; NK: natural killer; PRF1: perforin 1; SDC1: syndecan 1; SNAP29: synaptosome associated protein 29; SQSTM1: sequestosome 1; STX17: syntaxin 17; TGM2: transglutaminase 2; TME: tumor microenvironment; TGD: tumor growth delay; VAMP8: vesicle associated membrane protein 8; WT: wild type.

Breast cancer following metastatic dissemination is associated with high mortality rates, severely threatening women's health. As principal mediators of intercellular communication within the tumor microenvironment, secretory autophagosomes (SAPs) propel breast cancer progression and metastasis by modulating the establishment of the pre-metastatic niche, thereby positioning them as highly promising biomarkers for breast cancer. However, the paucity of accurate and simplified quantitative tools has impeded the direct detection of circulating SAPs. This study presents a sensing platform that couples nanozyme cascade catalysis with a covalent organic frameworks (COFs)-derived nanohydrogel (CGNH) for precisely assessing trace-level SAPs. The AuNBP@PtPd-MoS2 nanozyme, via its stereoconfiguration and trimetallic synergy, recapitulates the dual enzyme-mimicking activities of GOx/CAT. Hence, it enables self-sustained interfacial charge transfer. As a signal probe, it efficiently accelerates self-cascade catalysis and electrochemical mass transfer. Additionally, CGNH creates an ideal interface for SAPs enrichment and cascade catalysis, featuring a hierarchical pore structure, a hybrid conductive network, and suitable biocompatibility. With self-assembled antifouling peptide nanoparticles (APNP) as a shielding barrier, the platform reliably detects SAPs in intricate biological matrices verified using cellular, murine and clinical specimens. Compared with conventional biomarkers, SAPs produce more informative readouts on disease progression. This electrochemical platform differentiates between benign and malignant breast diseases and healthy controls with high diagnostic accuracy (AUC = 0.962), especially for gray-zone differentiation and metastasis forecasting. This study offers new avenues for SAPs-based liquid biopsy to identify signs of breast cancer metastasis and is expected to become a reliable non-invasive tool for personalized breast cancer management.

ABSTRACT Background Respiratory tract cancers account for a large proportion of new cancers and cause a major global health burden. Objective This study aimed to analyze global and regional trends in the incidence, mortality, and disability‐adjusted life years (DALYs) of these cancers from 1990 to 2021 and to project future burden to 2040. Methods We conducted a cross‐sectional analysis using data from the Global Burden of Disease 2021 study, assessing incidence, mortality, and DALYs globally and across 5 Socio‐demographic Index (SDI) regions, including risk factor attribution and health inequality trends. Findings In 2021, there were 2.60 million new cases globally. Between 1990 and 2021, incident cases, deaths, and DALYs increased by 95.01%, 60.48%, and 56.68%, respectively, while age‐standardized rates declined (estimated annual percentage change: −2.39%, −4.37%, −4.98%). By 2040, 2.45 million new cases are projected (67.11% male), with corresponding rates of 53.51, 46.90, and 1001.79 per 100 000. The highest age‐standardized burden was observed in high and high‐middle SDI regions. Smoking was the leading specific risk factor for deaths and DALYs, particularly for tracheal, bronchus, and lung cancer (TBLC) and laryngeal cancer (LC). Health inequalities increased from 1990 to 2021, especially for TBLC, with the slope inequality index for age‐standardized incidence rate, DALYs rate, and mortality rate rising from 36.54, 878.54, and 34.92 to 51.38, 953.63, and 44.52, respectively. Conclusion The absolute burden of respiratory tract cancers continues to rise despite declining rates, with significant inequalities. Enhanced, context‐specific prevention and control strategies are urgently needed.

Concurrent chemoradiotherapy is the standard treatment for inoperable, locally advanced esophageal cancer. However, older patients often have reduced tolerance to radiotherapy and concurrent intravenous chemotherapy due to declining physical function and multiple comorbidities. This prospective, single-center, phase II study assessed the efficacy and safety of nimotuzumab, an epidermal growth factor receptor antagonist, combined with concurrent radiotherapy and S-1 in patients 75 years and older. A total of 56 patients were enrolled, with the primary endpoint being progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate, disease control rate, treatment-related adverse events, nutritional indicators, and quality of life (QOL). Most nutritional indicators remained stable after treatment. As of June 2024, the median follow-up duration was 24.1 months (8.8-34.1). Eleven patients achieved complete response, 39 achieved partial response, five had stable disease, and one experienced progressive disease. The median PFS was 25.3 months (95% CI, 16.5-34.1), while the median OS was 28.2 months (95% CI, 24.1-32.3). Most adverse events were grade 1-2 (85.7%). Among survivors, 45.5% reported high satisfaction with their QOL, and 84.8% did not experience weight loss. This combination therapy demonstrated promising efficacy and safety, suggesting it may be a viable treatment option for this patient population.

Accurate prediction of local control (LC) following Gamma Knife radiosurgery (GKRS) remains clinically challenging for patients with brain metastases (BMs) secondary to breast or lung cancer. The scarcity of validated pre-therapeutic biomarkers currently hinders the development of individualized treatment decision-making strategies. This retrospective analysis included 324 BMs from 195 patients. To develop and benchmark various predictive frameworks, several models were constructed: clinical-only, radiomics-only, 2D deep learning (DL)-only, fused radiomics-DL (DLR), and a Combined model integrating all three modalities (clinical, radiomic, and DL features). All imaging signatures were derived from pre-treatment contrast-enhanced T1-weighted (T1CE) magnetic resonance imaging (MRI). Model performance was evaluated using the area under the curve (AUC), calibration plots, the Hosmer-Lemeshow test, and decision curve analysis (DCA). The Combined model demonstrated consistently high numerical discriminative performance, achieving an AUC of 0.854 (95

The management of cancer relies crucially on early diagnosis and personalized treatment. Real-time analysis of tumor markers within the tumor microenvironment via liquid biopsy opens potential pathways for effective cancer treatment and improved survival rates. Detecting low-abundance tumor markers in bodily fluids, particularly during early-stage cancer, poses significant challenges for traditional methods. Electrochemical sensors have emerged as the preferred technology for liquid biopsy. The exceptional multifunctionality of covalent organic frameworks (COFs)—novel crystalline porous organic polymer materials—has led to significant attention in electrochemical sensing; these features include tunable topologies, controllable pore sizes, and strong π-π stacking interactions. Recent advances in COF-based electrochemical sensors for liquid biopsy are summarized here, with details on COF design principles, synthesis and functionalization methods, and electrochemical reaction mechanisms. The focus is on the use of COFs as novel functional materials in electrochemical sensors for detecting tumor markers. Enhancement strategies for COF-based electrochemical sensors are also explored. An in-depth discussion on translating COF-based electrochemical sensors from laboratory achievements into clinical applications is also presented, covering the associated opportunities, challenges, and future research directions. The aim of this review is to offer concise yet profound guidance on the clinical translation of COF-based electrochemical analytical methods, which can contribute to advancing human health and precision diagnostics.

BACKGROUND:This phase II trial prospectively assessed the efficacy and safety of induction chemoimmunotherapy followed by sequential concurrent chemoradiotherapy plus immunotherapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were ineligible for surgery. METHODS:Forty-four patients received 2 cycles of induction therapy (paclitaxel plus carboplatin/nedaplatin combined with a PD-1 inhibitor), followed by concurrent radiotherapy with two additional cycles of chemoimmunotherapy and subsequent immune maintenance therapy for up to 1 year. The primary endpoint was progression-free survival (PFS); the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and quality of life (QoL). RESULTS:At the data cut-off point (median follow-up: 25.5 months), both the ORR and DCR were 95.5%. The median PFS was 26 months (95% CI, 14.8-37.2), and the median OS was 29 months (95% CI, 23.0-35.0). The 1-, 2-, and 3-year PFS rates were 75.0%, 51.9%, and 40.4%, respectively, and the OS rates were 81.8%, 63.1%, and 42.0%, respectively. Distant metastasis represented the main failure mode (64.0%). Treatment-related adverse events were generally mild; moreover, 17 patients (38.6%) experienced grade ≥3 events, primarily involving hematologic toxicity (14/17). Severe immune-related adverse events were rarely observed. QoL assessment in surviving patients (n = 21) indicated favorable overall function and well-being. CONCLUSIONS:This regimen of induction chemoimmunotherapy followed by concurrent chemoradiotherapy and maintenance immunotherapy demonstrated promising survival outcomes, a manageable safety profile, and a preserved QoL, thereby offering a viable nonsurgical alternative for patients with locally advanced ESCC.

Radiation-induced skin toxicity, resulting from ionizing or nonionizing radiation, is a common skin disorder. However, the underlying relationship between skin microbiota and radiation-induced skin toxicity remains largely unexplored. Herein, we uncover the microbiota–skin interaction based on a genome-wide association study (GWAS) featuring 150 skin microbiota and three types of skin microenvironment. Summary datasets of human skin microbiota were extracted from the GWAS catalog database, and summary datasets of radiation-induced skin toxicity from the FinnGen biobank. Mendelian Randomization (MR) analysis was leveraged to sort out the causal link between skin microbiota and radiation-induced skin toxicity. We identified 33 causal connections between human skin microbiota and radiation-induced skin toxicity, including 19 positive and 14 negative causative directions. Among these potential associations, the genus Staphylococcus could serve as a common risk factor for radiation-induced skin toxicity, especially for radiodermatitis. And Streptococcus salivarius was identified as a potential protective factor against radiation-induced skin toxicity. Additional analysis indicated no pleiotropy, heterogeneity, or reverse causal relationship in the results. We comprehensively assessed potential associations of skin microbiota with radiation-induced skin toxicity and identified several suggestive links. Our results provide promising targets for the prevention and treatment of radiation-induced skin toxicity.

This study aims to evaluate the clinical effectiveness of trilaciclib in preventing myelosuppression in patients with esophageal cancer undergoing chemotherapy. Based on the use of trilaciclib, 81 patients were divided into a primary prevention group (PP group, n = 49) and a secondary prevention group (SP group, n = 32). The incidence of myelosuppression, antibiotic usage rate, survival outcomes, and other treatment-related toxicities were analyzed using chi-square tests and Kaplan–Meier survival curves. The incidence of chemotherapy-induced myelosuppression in the SP group was significantly higher than that in the PP group (96.9% vs. 79.6%), with a significantly higher proportion of grade III and above events (37.6% vs. 8.2%, p < 0.05). For chemotherapy-induced neutropenia, the incidence of grade III/IV events in the SP group was significantly higher than in the PP group (28.1% vs. 8.2%, p = 0.017). Additionally, the SP group experienced higher rates and severity of chemotherapy-induced anemia and thrombocytopenia. The PP group provided better protection against grade III/IV leukopenia and neutropenia (p < 0.05). Non-hematological toxicities and efficacy outcomes were similar between groups (p > 0.05). The study is the first to demonstrate that trilaciclib is a safe and effective option for the prevention of myelosuppression in esophageal cancer patients.

OBJECTIVE:Current staging systems classify distant lymph node metastasis (DLM) in cervical cancer as stage IVB, typically treated with systemic therapy. We aim to assess if patients with DLM have different survival rates than those with other stage IVB cervical cancer forms. METHODS:This study included patients diagnosed with metastatic cervical cancer from 2000 to 2021, divided into three groups: para-aortic lymph node metastasis (PaLM), DLM, and distant organ metastasis (DM). Kaplan-Meier analyses estimated cervical cancer-specific (CCSS) and overall survival (OS). A 1:1 propensity-score match between DLM and PaLM patients used logistic regression. Univariate and multivariate Cox analyses identified prognostic risk factors. RESULTS:Of the included 6241 patients, 2079 (33.3 %) were diagnosed with PaLM only, 631 (10.1 %) with DLM only, and 3531 (56.6 %) had DM. Multivariate Cox regression analysis indicated that patients with DLM exhibited comparable CCSS (HR, 0.91; P = 0.28) and OS (HR, 0.93; P = 0.34) to those with PaLM. In contrast, compared to patients with DM, the DLM cohort demonstrated significantly improved CCSS (HR, 0.54; P < 0.001) and OS (HR, 0.58; P < 0.001). Following matching, the CCSS (HR, 0.96; P = 0.70) and OS (HR, 0.95; P = 0.61) of patients with DLM remained comparable to those with PaLM. Among the 632 patients with DLM, locoregional treatments such as total hysterectomy (HR, 0.46; P = 0.039) and radiotherapy (HR, 0.34; P = 0.046) were independently associated with improved OS. CONCLUSION:In cervical cancer, metastasis confined to distant lymph nodes indicates a locoregionally advanced stage, distinct from other stage IVB forms, and can be treated curatively with intensive locoregional therapy.

Lactylation, as a novel post-translational modification, has gained a lot of attention in the biomedical field in recent years. Lactylation is not only related to cellular metabolism but also increasingly prominent in the tumor microenvironment, particularly in regulating radiation sensitivity. This review aims to explore the potential connection between lactylation modification and the regulation of radiation sensitivity. Current research shows that lactylation might be crucial in how tumor cells respond to radiotherapy by influencing energy metabolism, gene expression, and cell signaling. However, despite preliminary studies revealing the association between lactylation and radiation sensitivity, the understanding of its specific mechanisms remains insufficient, necessitating more systematic research to elucidate this process. Therefore, by analyzing the biological basis of lactylation modification, its role in tumor metabolism, and its relationship with radiotherapy, we summarize the importance and application prospects of lactylation in tumor treatment, providing direction for future research.

Lactate, a byproduct of glycolysis, was first identified to induce a novel post-translational modification (PTM) known as lysine lactylation (Kla) in 2019. Kla has been shown to regulate various biological processes, including transcription, metabolism, cell proliferation, and inflammatory responses, which are pivotal in both tumorigenesis and cellular aging. Initially, Kla was identified as an epigenetic marker on histones, where it regulates gene transcription. However, more recent studies have demonstrated widespread Kla modifications on non-histone proteins, suggesting their involvement in multiple tumorigenic processes, which are often dysregulated during aging. Unlike histone Kla, which influences gene accessibility and transcription, non-histone protein Kla exerts a more direct influence on protein levels and functions by modifying their stability, activity, or localization. This review summarizes the latest advances in non-histone Kla research, highlighting its regulatory factors and role in tumor biology and treatment resistance. Additionally, we discuss the potential implications of non-histone Kla in tumor diagnosis, prognosis, and targeted therapy.

BACKGROUND:The optimal regimen and chemotherapy intensity are still under investigation for neoadjuvant treatment of locally advanced rectal cancer (LARC). The CinClare trial has demonstrated improved pathologic complete response (pCR) with the addition of irinotecan to neoadjuvant chemoradiotherapy (CRT) guided by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype in LARC. Here, we report the 5-year follow-up outcomes of the CinClare study. METHODS:From November 2015 to December 2017, this randomized, open-label, multicenter, phase III trial enrolled 360 patients with LARC and assigned them in a 1:1 ratio to CapIriRT (radiation with capecitabine combined with irinotecan followed by irinotecan and capecitabine) or CapRT (radiation with concurrent capecitabine followed by oxaliplatin and capecitabine). Irinotecan dosing was guided by UGT1A1 genotype (80 mg/m2 for *1/*1 and 65 mg/m2 for *1/*28). The endpoints, including local control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS), were analyzed using the log-rank test, Cox proportional hazards regression and restricted mean survival time (RMST) test at the data cut-off date of June 2023. RESULTS:With a median follow-up of 60 months, the CapIriRT group showed numerically higher 5-year LC (95.6% vs. 93.9%), 5-year DMFS (83.9% vs. 77.9%), 5-year DFS (77.7% vs. 70.6%), and 5-year OS rates (82.9% vs. 76.1%) than the CapRT group. Further RMST test also showed a statistically significant difference in DFS (P < 0.05) and a borderline difference in OS (P = 0.050). Among the UGT1A1 *1/*1 population, the CapIriRT group had significantly improved 5-year rates of DMFS, DFS, and OS (all P < 0.05). Patients achieving pCR also had significantly longer DFS and OS compared to non-pCR patients (P < 0.05). CONCLUSIONS:The addition of irinotecan guided by UGT1A1 genotype to a standard capecitabine-based scheme brings clinical benefits with improved LC, DMFS, DFS, and OS. Patients with the UGT1A1 *1/*1 genotype derived notable benefit from irinotecan, with improved survival outcomes. Achievement of pCR is crucial as it is associated with improved long-term survival. These findings support the integration of genomic testing into clinical practice to achieve a personalized irinotecan dosing regimen, which can optimize efficacy and safety. TRIAL REGISTRATION:ClinicalTrials.gov (NCT02605265).

OBJECTIVE:To evaluate the effects of whole-course immunonutrition management (WIM) on patients with stage III and IV nasopharyngeal carcinoma (NPC) undergoing radiotherapy. METHODS:A total of 103 patients with NPC admitted to our hospital between October 2021 and June 2023 were assigned to receive either conventional nursing (routine group, n = 51) or WIM therapy (experimental group, n = 52) according to different nursing methods. Outcome measures included nutritional status assessment, haematological indicators, adverse reactions and the social support situation. RESULTS:Following the intervention, the WIM approach was associated with a significantly lower incidence of adverse reactions compared with routine nursing care (p < 0.05). Specifically, the experimental group had a significantly lower incidence of nausea (p = 0.0341), vomiting (p = 0.0279) and high-level oral mucositis (III/IV) (p = 0.0238) compared with the routine group. In terms of the nutritional status, patients in the experimental group maintained better body mass index (BMI) and body weight, with significant differences observed in total protein levels (p < 0.05) throughout the trial, indicating improved nutritional outcomes. However, no significant differences were found in the changes of BMI between the two groups. The social support situation was also significantly better in the experimental group, as evidenced by a greater improvement in the social support rating scale scores (p = 0.0017). CONCLUSIONS:Whole-course immunonutrition management can improve the nutritional status of patients with NPC treated with concurrent chemoradiotherapy, reduce the severity of radiation-induced nasopharyngeal and oral reactions and relieve side effects.

PURPOSE:This study reports the long-term outcomes of simultaneous integrated boost radiotherapy (SIB-RT) combined with oral S-1 chemotherapy (CRTCT) in inoperable patients aged ≥ 70 years with inoperable esophageal squamous cell carcinoma (ESCC). METHODS:In this multicenter, phase III randomized trial, patients with inoperable, locally advanced stage II-IV ESCC were randomized to receive either CRTCT or RT alone. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), restricted mean survival time (RMST), and patterns of failure. RESULTS:After a median follow-up of 75 months, patients in the CRTCT group had longer OS than those in the RT group (hazard ratio (HR), 0.74; 95 % confidence interval (CI), 0.57-0.95; P = 0.02), with better 5-year OS rates (34.1 % vs. 23.6 %,P = 0.02), PFS (31.1 % vs. 20.9 %,P = 0.02), and RMST (33.0 vs. 27.0 months,P = 0.02). CRTCT's effect on OS stabilized over 5 years. Locoregional failure was lower in the CRTCT group (HR, 0.64; 95 % CI, 0.45-0.92; P = 0.02), with similar distant and mixed failure risks. CONCLUSIONS:SIB-RT combined with oral S-1 chemotherapy significantly improved long-term survival and therefore might be considered a standard of care for elderly patients with inoperable ESCC. TRIAL REGISTRATION Clinical Trials.gov Identifier: NCT0297969.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy of the digestive system. Hypoxia is a crucial player in tumor ferroptosis resistance. However, the molecular mechanism of hypoxia-mediated ferroptosis resistance in ESCC remains unclear. Here, USP2 expression was decreased in ESCC cell lines subjected to hypoxia treatment and was lowly expressed in clinical ESCC specimens. Ubiquitin-specific protease 2 (USP2) depletion facilitated cell growth, which was blocked in USP2-overexpressing cells. Moreover, USP2 silencing enhanced the iron ion concentration and lipid peroxidation accumulation as well as suppressed ferroptosis, while upregulating USP2 promoted ferroptotic cell death in ESCC cells. Furthermore, knockout of USP2 in ESCC models discloses the essential role of USP2 in promoting ESCC tumorigenesis and inhibiting ferroptosis. In contrast, overexpression of USP2 contributes to antitumor effect and ferroptosis events in vivo. Specifically, USP2 stably bound to and suppressed the degradation of nuclear receptor coactivator 4 (NCOA4) by eliminating the Lys48-linked chain, which in turn triggered ferritinophagy and ferroptosis in ESCC cells. Our findings suggest that USP2 plays a crucial role in iron metabolism and ferroptosis and that the USP2/NCOA4 axis is a promising therapeutic target for the management of ESCC.

BACKGROUND:The treatment strategy for recurrent or metastatic esophageal squamous cell carcinoma (ESCC) is immunotherapy-based systemic treatment. The effect of local radiotherapy on the survival of recurrent or metastatic ESCC patients is unclear. This work is aimed to investigate the efficacy of local radiotherapy in combination with immunotherapy-based systemic therapy. METHODS:In this retrospective observational study, data were collected from recurrent or metastatic ESCC patients treated at the Radiotherapy Department of Jiangsu Province Hospital between March 2019 and December 2022. This study enrolled a total of 73 patients with recurrent or metastatic ESCC. The overall survival (OS) of all patients and OS stratified by different treatment patterns were analyzed. Prognostic factors influencing OS were examined using uni- and multi-variate Cox tests. RESULTS:The median OS of the study population was 21.4 (95%CI: 13.7-29.1) months. The median OS of patients who received radiotherapy in additional to systemic therapy was 31.5 (13.5-49.5) months, while the patients who received systemic therapy alone had a significantly shorter median OS of 10.7 (95%CI: 8.0-13.4) months. OS was also significantly different among patients receiving different cycles of immunotherapy. The median OS of patients after 1-6 cycles of immunotherapy was 14.6 (95%CI: 11.3-18.0) months, that after 7-12 cycles was 21.1 (95%CI: 0-43.8) months, and that after more than 12 cycle was 52.1 (25.6-78.6) months. CONCLUSIONS:In the first-line therapy of recurrent or metastatic ESCC based on immunotherapy, the addition of local radiotherapy significantly improves patient survival. As the number of immunotherapy cycles increases, the survival benefits become more pronounced.