Gemcitabine and cisplatin (GP) serve as first-line induction chemotherapy (IC) for nasopharyngeal carcinoma (NPC), yet predictive markers are lacking. Here we performed multi-omics profiling, including proteomics, phosphoproteomics, genomics and transcriptomics, on 240 patients with NPC who were receiving GP-IC or concurrent chemoradiotherapy (CCRT) alone. Through multi-omic integration, we identified three proteomic subtypes with distinct therapeutic vulnerabilities. The S1 subtype showed a predominant interferon-γ response and had favorable outcomes with CCRT alone. The S2 subtype featured copy-number-driven cell cycle activation, deriving benefits from GP-IC. The immune-exhausted S3 subtype exhibited high IgA+ plasma cell infiltration and was resistant to GP-IC but responded to anti-PD-1 therapy. Single-cell RNA sequencing confirmed interaction between IgA+ plasma cells and CD8+ T cells in nonresponders. Validation from three phase III trials and spatial analyses demonstrated that high IgA+ plasma cell infiltration predicted GP-IC resistance but benefited from anti-PD-1 therapy. This study delineates a subtype-specific landscape of GP-IC response and may inform personalized treatment in NPC.

The nasopharynx constitutes a critical niche in the upper respiratory tract, harboring a diverse microbiota linked to nasopharyngeal carcinoma (NPC), the mechanistic roles of which remain poorly understood. Here, we established the Nasopharyngeal Mucosal and Tumor-resident Bacterial Catalog (NMTBC) that comprises 5311 bacterial isolates representing 127 species, with 1006 of them being fully sequenced and annotated, providing a comprehensive culturable resource facilitating mechanistic dissection of the microbiome-tumor interactions. With NMTBC, we uncovered a Fusobacterium-Prevotella mutualism and revealed heterotypic bacterium-bacterium interactions involving transcriptional reprogramming and metabolic cross-talk. Using single-bacterial transcriptomics, we mapped a high-resolution transcriptomic trajectory, showing the ability of a single strain to differentiate into functionally distinct subpopulations that cooperate to sustain mutualism. By analyzing a multicenter NPC cohort, we showed that Fusobacterium and Prevotella co-colonization in NPC tumors correlated with unfavorable clinical outcomes after conventional radiochemotherapy. Analysis of RNA-seq data from two previous phase 3 clinical trials showed that coenrichment of Fusobacterium-Prevotella predicted better response to anti-PD-1 immunotherapy, highlighting their important role in microbiota-mediated immunomodulation. Overall, this study establishes a comprehensive nasopharyngeal bacterial catalog through culturomics, which offers valuable insights into microbiome-derived biomarker discovery and immunotherapy patient stratification in clinical practice.

PURPOSEPersonalized immunotherapy strategies are urgently needed for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We aim to identify biomarkers predictive of immunotherapy benefits, using data from the phase III CONTINUUM (ClinicalTrials.gov identifier: NCT03700476) and DIPPER (ClinicalTrials.gov identifier: NCT03427827) randomized clinical trials.PATIENTS AND METHODSTumor samples from 407 patients in the CONTINUUM (discovery cohort) and DIPPER (validation cohort) trials were subjected to RNA sequencing. In the discovery cohort, metabolic gene-based consensus clustering was performed to determine subtypes. A machine learning-based classifier was subsequently developed in the discovery cohort and then applied to the validation cohort to assign metabolic subtypes. Gene set enrichment analyses were used to characterize the biological features of each metabolic subtype. The clinical end point was event-free survival (EFS).RESULTSIn the discovery cohort, three metabolic subtypes were identified with distinct tumor-intrinsic and immune features as well as differential EFS benefits from adding anti-PD-1 to chemoradiotherapy (CRT). Specifically, the MS1 subtype exhibited a significant improvement in 3-year EFS in the anti-PD-1 plus CRT arm compared with the CRT-alone arm (3-year EFS, 90.2% v 69.6%; hazard ratio, 0.27 [95% CI, 0.11 to 0.67]), whereas MS2 (3-year EFS, 94.1% v 93.8%) and MS3 subtypes (3-year EFS, 75.0% v 75.0%) derived no significant survival benefit. The subtype features were preserved in the validation cohort, with consistent prognostic and predictive value. A pooled analysis of both cohorts demonstrated the significant interaction between metabolic subtypes and the treatment effect (Pinteraction = 0.0074).CONCLUSIONIn this biomarker study, we defined metabolic subtypes of NPC that predicted the EFS benefit from immunotherapy. This novel molecular classification provides a promising predictive biomarker for personalized treatment decision for patients with locoregionally advanced NPC.

Chemoresistance is a primary factor limiting nasopharyngeal carcinoma (NPC) treatment. Growing evidence indicates that E3 ubiquitin ligases play a pivotal role in chemoresistance. Here, we identified that the E3 ubiquitin ligase RNF138 is significantly upregulated in NPC patients who do not respond to chemotherapy. Our study reveals that RNF138 promotes the K48-linked ubiquitination of hnRNPA0 at K133, thereby destabilizing WWOX mRNA. The subsequent loss of WWOX protein relieves the inhibition of JAK2 self-phosphorylation, leading to constitutive pathway activation. Consequently, RNF138-JAK2/STAT3 activation suppresses chemotherapy-induced apoptosis via reduced ROS production and promotes immune evasion by upregulating PD-L1. Clinically, high RNF138 expression correlated with poor prognosis and resistance to chemotherapy. In conclusion, this study unveils the RNF138-hnRNPA0-WWOX axis as a driver of JAK2/STAT3 activation, leading to both chemoresistance and immune evasion in NPC. This work positions RNF138 as a valuable biomarker to guide individualized chemotherapy, and highlights JAK inhibitors as a potential targeted therapy for NPC patients.

6060 Background: Treatment options are limited and clinical outcomes remain unsatisfactory for patients with recurrent/metastatic nasopharyngeal carcinoma (r/m NPC) in the later-line setting. HLX43 is a novel anti-programmed cell death-ligand 1 (PD-L1) antibody-drug conjugate with promising antitumor activity in advanced tumors. Here we present results from a phase 2 study evaluating HLX43 in previously treated r/m NPC. Methods: This randomized, multicenter trial enrolled patients with histologically or cytologically confirmed r/m NPC who had received at least second-line chemotherapy (including one prior line of platinum-based chemotherapy) and progressed on or were intolerant to programmed death (ligand) 1 (PD-[L]1) inhibitor. Patients were randomized 1:1:1 to receive 2 mg/kg, 2.5 mg/kg, or 3 mg/kg of intravenous HLX43 every 3 weeks. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) per investigator's assessments. Results: As of September 18, 2025, 30 patients were randomized to the 2, 2.5, or 3 mg/kg group ( n = 10 for each group). The median follow-up duration was 2.8 months (range 2.1–5.6). Twenty-six patients (86.7%) had performance status 1; 27 (90.0%) had prior radiotherapy. The median line of prior systemic therapy was 3 (range 2–8). ORR was 36.7%, with partial responses (PRs) in 11 patients. ORR in the three dose groups was 20.0%, 20.0% and 70.0% (all confirmed by December 2025), respectively; disease control rate (DCR) was 50.0%, 50.0% and 80.0%. PFS data were immature. Overall, treatment-emergent adverse events (TEAEs) occurred in 29 patients (96.7%; grade ≥3, 50.0%). TEAE incidence was 90.0%, 100% and 100% in the three dose groups, respectively. TEAE leading to dose reduction was reported in 3 patients (30.0%) in the 3 mg/kg group only. TEAE leading to treatment discontinuation occurred in 1 (10.0%) each in the 2.5 mg/kg and 3 mg/kg groups. There was no death due to TEAE. The efficacy and safety findings are detailed in Table 1. Conclusions: HLX43 showed promising efficacy with a manageable safety profile in r/m NPC patients who had progressed after second-line or later chemotherapy and PD-(L)1 inhibitors. Further investigation is warranted. Clinical trial information: NCT06839066 . Efficacy and safety. 2.0 mg/kgN=10 2.5 mg/kgN=10 3.0 mg/kgN=10 TotalN=30 PR 2 (20.0) 2 (20.0) 7 (70.0) 11 (36.7) SD 3 (30.0) 3 (30.0) 1 (10.0) 7 (23.3) PD/NE 5 (50.0) 5 (50.0) 2 (20.0) 12 (40.0) ORR, 95% CI (%) 20.0(2.5, 55.6) 20.0(2.5, 55.6) 70.0(34.8, 93.3) 36.7(19.9, 56.1) DCR, 95% CI (%) 50.0(18.7, 81.3) 50.0(18.7, 81.3) 80.0(44.4, 97.5) 60.0(40.6, 77.3) TEAEs 9 (90.0) 10 (100) 10 (100) 29 (96.7) Grade ≥3 TEAEs 2 (20.0) 7 (70.0) 6 (60.0) 15 (50.0) TEAE leading to dose reduction 0 0 3 (30.0) 3 (10.0) TEAE leading to treatment discontinuation 0 1 (10.0) 1 (10.0) 2 (6.7) NE, not evaluable. PD, progressive disease. SD, stable disease.

Growing evidence highlights the existence and tumor-promoting role of intratumoral bacteria in various types of cancers. However, the mechanisms enabling the intracellular survival of these microorganisms remain poorly understood, impeding the development of microbiota-targeting anticancer strategies. A transcriptomics analysis was used to identify the disease-related bacteria in nasopharyngeal carcinoma (NPC). Cell-bacteria coculture assay, cell viability assay, and mouse xenograft tumor model were used for functional investigation. Immunofluorescence, quantitative PCR analysis, RNA sequencing, immunoblot analysis, co-immunoprecipitation and mass spectrometry were utilized in mechanistic research. Fluorescent in situ hybridization in NPC specimens and clinical data were used for prognosis analysis. We discovered that the Fusobacterium nucleatum (F. nucleatum), especially the C2 clade of F. nucleatum subsp. animalis (Fna C2), acts as an intracellular pathogen and exhibits distinct colonization advantages in NPC by inhibiting autophagy flux in host cells. Mechanistically, the virulence protein FadA of Fna C2 increases the ubiquitination and promotes the degradation of Ras-related protein RAB7A by enhancing the interaction between RAB7A and the E3 ligase TRIM28, which thus impairs the autophagosome-lysosome fusion and the autophagy machinery. The dysfunctional autophagy not only enables the persistent intracellular survival of F. nucleatum but also contributes to the treatment resistance of NPC. Clinically, a high intratumoral F. nucleatum colonization is associated with tumor relapse and poor outcome in NPC patients. Our findings elucidate a key mechanism by which F. nucleatum survives and promotes treatment resistance in NPC, providing a microbiological prognosis indicator for NPC patients.

The value of microbial metabolites in prognosis and treatment response prediction in patients with nasopharyngeal carcinoma (NPC) remains unclear. Here, through the untargeted metabolomic analysis of plasma in 48 paired NPC patients with or without tumor relapse, we identified distinct circulating metabolite atlases between NPC patients with different prognoses. We used bootstrap least absolute shrinkage and selection operator (LASSO) on a penalized Cox regression model to select metabolites and constructed a metabolite risk model comprising four microbial metabolites in a training cohort (n = 202), and validated it in an independent test cohort (n = 201) and an external validation cohort (n = 180). The model stratified patients into three risk groups. Patients in the low-risk group had optimal DFS, DMFS, and OS, compared with those in the intermediate-risk group. High-risk patients had poor survival across all clinical endpoints. Furthermore, patients in the intermediate-risk group could benefit from induction chemotherapy. In addition, we generated a nomogram integrating the risk model, N stage, and plasma EBV-DNA load, which further enhanced the predictive accuracy of the metabolite risk model. Collectively, we developed and validated a robust predictive model based on serum metabolites, promoting risk stratification and enhancing treatment outcomes in patients with NPC. We identified distinct circulating metabolite atlases between NPC patients with different prognoses in the training cohort (n = 202). A risk model, comprising four microbial metabolites, was developed to stratify patients into three risk groups. Patients in the low-risk group had optimal DFS, DMFS, and OS, compared with those in the intermediate-risk group. High-risk patients had poor survival across all clinical endpoints. Findings were validated using an independent test cohort (n = 201) and an external validation cohort (n = 180). Specifically, a nomogram integrating the risk model, N stage, and plasma EBV-DNA load enhanced predictive accuracy. Moreover, patients benefited from induction chemotherapy with improved survival in the intermediate-risk group, but not in the low-risk and high-risk groups.

Supplementary Figure from CircIPO7 Promotes Nasopharyngeal Carcinoma Metastasis and Cisplatin Chemoresistance by Facilitating YBX1 Nuclear Localization

Emerging evidence reveals that microbiota plays a crucial role in multiple cancers. Nasopharyngeal carcinoma (NPC) tissues harbour microbiota, highlighting the need to investigate the clinical implications of tissue-resident microbiota in the development of NPC. Here, we aim to clarify the specific profile of tissue-resident microbiota and its influence on NPC outcomes. This retrospective study included 491 NPC patients from Sun Yat-sen University Cancer Center (Guangzhou, China) and the Affiliated Hospital of Guilin Medical College (Guilin, China). We profiled the microbial composition of 343 NPC and 36 normal nasopharyngeal tissues through sequencing of the genes encoding the 16S rRNA subunit of bacterial ribosomes. There were significant differences in microbial composition, alpha diversity (Shannon index, P = 0.007; Simpson index, P = 0.036), and beta diversity (Bray–Curtis distance: R2 = 0.016, F = 5.187, P = 0.001; unweighted UniFrac distance: R2 = 0.017, F = 5.373, P = 0.001) between NPC and normal nasopharyngeal tissues. A bacterial signature comprising four risk bacterial genera, including Bacteroides, Alloprevotella, Parvimonas, and Dialister, was constructed in the training cohort (n = 171). Patients in the high-risk group had shorter disease-free (HR 2.80, 95

The introduction of PD-1 blockades to chemotherapy and radiotherapy has shown promising outcomes in patients with nasopharyngeal carcinoma, but anti-PD-1 therapies are only effective in a small proportion of patients, indicating the need for reliable predictive biomarkers of benefit from immunotherapy. Here, we summarized recent advances in immunotherapy for nasopharyngeal carcinoma and studies on potential predictors that correlated with treatment response or long-term survival after immunotherapy, including biomarkers in both the tumor microenvironment and the tumor macroenvironment. Some of these biomarkers have been validated as truly predictive of immunotherapy benefit using cohorts from randomized controlled trials, while others still require further validation of their predictive value. We also summarized the challenges and future directions of biomarker studies, hopefully facilitating the development of predictive biomarkers for immunotherapy that can eventually enter clinical practice.

Approximately 20% to 30% of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) experience disease relapse despite definitive chemoradiotherapy. The programmed cell death 1 (PD-1) blockade camrelizumab has demonstrated considerable value in recurrent or metastatic NPC, while its role in locoregionally advanced NPC is unclear. To evaluate the efficacy and safety of adjuvant camrelizumab for patients with locoregionally advanced NPC. Randomized, open-label, multicenter, phase 3 clinical trial conducted from August 2018 to November 2021 at 11 centers in China and enrolling 450 patients with T4N1M0 or T1-4N2-3M0 NPC who had completed induction-concurrent chemoradiotherapy. The final date of follow-up was March 20, 2024. Patients were randomized (1:1) to receive adjuvant camrelizumab (200 mg intravenously once every 3 weeks for 12 cycles; n = 226) or observation (standard therapy group; n = 224). The primary end point was event-free survival (freedom from distant metastasis, locoregional relapse, or death due to any cause). Secondary end points included distant metastasis–free survival, locoregional relapse–free survival, overall survival, safety, and health-related quality of life. Among the 450 participants (mean age, 45 [SD, 10] years; 24% women), after a median follow-up of 39 (IQR, 33-50) months, the camrelizumab group had a 3-year event-free survival rate of 86.9%, whereas the standard therapy group had a rate of 77.3% (stratified hazard ratio, 0.56; 95% CI, 0.36-0.89; P = .01). Grade 3 or 4 adverse events were reported in 23 patients (11.2%) in the camrelizumab and 7 (3.2%) in the standard therapy group. Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab, occurring in 85.8% of patients at grade 1 or 2, while 2% of patients had grade 3 or 4 events. There was no significant deterioration in quality of life associated with camrelizumab treatment. Adjuvant PD-1 blockade with camrelizumab significantly improved event-free survival with manageable toxicities, highlighting its potential role in the management of locoregionally advanced NPC. ClinicalTrials.gov Identifier: NCT03427827

Importance With the programmed cell death protein 1 (PD-1) blockade toripalimab, omitting highly toxic concurrent cisplatin may be feasible for nasopharyngeal carcinoma (NPC) without compromising survival. Objective To evaluate the efficacy and safety of toripalimab incorporated into induction chemotherapy and radiotherapy, without concurrent cisplatin, for locoregionally advanced NPC. Design, Setting, and Participants Open-label, multicenter, randomized phase 3 clinical trial conducted from August 2021 to July 2022 at 13 hospitals in China, enrolling 532 patients with T4N1M0 or T1-4N2-3M0 NPC; 400 (75.2%) completed the trial per protocol. The final date of follow-up was March 21, 2025. Interventions Patients were randomly assigned to either the standard therapy group (n = 266), receiving toripalimab with gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin-radiotherapy (100 mg/m(2) triweekly for 2 cycles), or the concurrent cisplatin-sparing group (n = 266), receiving the same regimen without concurrent cisplatin. The 17 cycles of toripalimab (240 mg triweekly) were distributed across the induction, radiotherapy, and adjuvant phases as 3, 3, and 11 cycles, respectively. Main Outcomes and Measures Coprimary end points were failure-free survival (noninferiority margin, 8%) and incidence of all-grade vomiting (superiority design). Secondary end points included overall survival, locoregional recurrence-free survival, distant metastasis-free survival, safety, tumor response, quality of life, and tolerability. Results In the 532 patients in the intention-to-treat population (median [IQR] age, 47 [39-54] years; 25.2% women), after a median follow-up of 37.0 (range, 4.0-50.0) months, the concurrent cisplatin-sparing group had a 3-year failure-free survival rate of 88.3% vs 87.6% in the standard therapy group, a difference of 0.7% (lower limit of the 1-sided 95% CI, -3.9%; P = .002 for noninferiority; stratified hazard ratio, 0.92 [95% CI, 0.66-1.79]; log-rank P = .73). In the safety analysis, the incidence of all-grade vomiting was significantly lower in the concurrent cisplatin-sparing group vs the standard therapy group (26.2% [68/260] vs 59.8% [156/261]; difference, 33.6% [1-sided 95% CI, 26.9%-infinity]; P < .001). Patient-reported quality of life (participation rate, 87.5%) and tolerability (participation rate, 94.7%) were better in the concurrent cisplatin-sparing group, primarily in gastrointestinal, functional, and global health status. Conclusions and Relevance In this phase 3 randomized clinical trial, among patients with locoregionally advanced NPC, toripalimab combination therapy without concurrent cisplatin was a feasible treatment with high efficacy in failure-free survival and low toxicity. Trial Registration ClinicalTrials.gov Identifier: NCT04907370

Importance Approximately 20% to 30% of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) experience disease relapse despite definitive chemoradiotherapy. The programmed cell death 1 (PD-1) blockade camrelizumab has demonstrated considerable value in recurrent or metastatic NPC, while its role in locoregionally advanced NPC is unclear. Objective To evaluate the efficacy and safety of adjuvant camrelizumab for patients with locoregionally advanced NPC. Design, Setting, and Participants Randomized, open-label, multicenter, phase 3 clinical trial conducted from August 2018 to November 2021 at 11 centers in China and enrolling 450 patients with T4N1M0 or T1-4N2-3M0 NPC who had completed induction-concurrent chemoradiotherapy. The final date of follow-up was March 20, 2024. Interventions Patients were randomized (1:1) to receive adjuvant camrelizumab (200 mg intravenously once every 3 weeks for 12 cycles; n = 226) or observation (standard therapy group; n = 224). Main Outcomes and Measures The primary end point was event-free survival (freedom from distant metastasis, locoregional relapse, or death due to any cause). Secondary end points included distant metastasis-free survival, locoregional relapse-free survival, overall survival, safety, and health-related quality of life. Results Among the 450 participants (mean age, 45 [SD, 10] years; 24% women), after a median follow-up of 39 (IQR, 33-50) months, the camrelizumab group had a 3-year event-free survival rate of 86.9%, whereas the standard therapy group had a rate of 77.3% (stratified hazard ratio, 0.56; 95% CI, 0.36-0.89; P = .01). Grade 3 or 4 adverse events were reported in 23 patients (11.2%) in the camrelizumab and 7 (3.2%) in the standard therapy group. Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab, occurring in 85.8% of patients at grade 1 or 2, while 2% of patients had grade 3 or 4 events. There was no significant deterioration in quality of life associated with camrelizumab treatment. Conclusions and Relevance Adjuvant PD-1 blockade with camrelizumab significantly improved event-free survival with manageable toxicities, highlighting its potential role in the management of locoregionally advanced NPC.

With the programmed cell death protein 1 (PD-1) blockade toripalimab, omitting highly toxic concurrent cisplatin may be feasible for nasopharyngeal carcinoma (NPC) without compromising survival. To evaluate the efficacy and safety of toripalimab incorporated into induction chemotherapy and radiotherapy, without concurrent cisplatin, for locoregionally advanced NPC. Open-label, multicenter, randomized phase 3 clinical trial conducted from August 2021 to July 2022 at 13 hospitals in China, enrolling 532 patients with T4N1M0 or T1-4N2-3M0 NPC; 400 (75.2%) completed the trial per protocol. The final date of follow-up was March 21, 2025. Patients were randomly assigned to either the standard therapy group (n = 266), receiving toripalimab with gemcitabine-cisplatin induction chemotherapy and concurrent cisplatin-radiotherapy (100 mg/m2 triweekly for 2 cycles), or the concurrent cisplatin–sparing group (n = 266), receiving the same regimen without concurrent cisplatin. The 17 cycles of toripalimab (240 mg triweekly) were distributed across the induction, radiotherapy, and adjuvant phases as 3, 3, and 11 cycles, respectively. Coprimary end points were failure-free survival (noninferiority margin, 8%) and incidence of all-grade vomiting (superiority design). Secondary end points included overall survival, locoregional recurrence-free survival, distant metastasis–free survival, safety, tumor response, quality of life, and tolerability. In the 532 patients in the intention-to-treat population (median [IQR] age, 47 [39-54] years; 25.2% women), after a median follow-up of 37.0 (range, 4.0-50.0) months, the concurrent cisplatin–sparing group had a 3-year failure-free survival rate of 88.3% vs 87.6% in the standard therapy group, a difference of 0.7% (lower limit of the 1-sided 95% CI, −3.9%; P = .002 for noninferiority; stratified hazard ratio, 0.92 [95% CI, 0.66-1.79]; log-rank P = .73). In the safety analysis, the incidence of all-grade vomiting was significantly lower in the concurrent cisplatin–sparing group vs the standard therapy group (26.2% [68/260] vs 59.8% [156/261]; difference, 33.6% [1-sided 95% CI, 26.9%-∞]; P < .001). Patient-reported quality of life (participation rate, 87.5%) and tolerability (participation rate, 94.7%) were better in the concurrent cisplatin–sparing group, primarily in gastrointestinal, functional, and global health status. In this phase 3 randomized clinical trial, among patients with locoregionally advanced NPC, toripalimab combination therapy without concurrent cisplatin was a feasible treatment with high efficacy in failure-free survival and low toxicity. ClinicalTrials.gov Identifier: NCT04907370

The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC.

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system. While chemotherapy may initially be effective in patient with nasopharyngeal carcinoma (NPC), resistance often develops. Here, the authors identify PJA1 as a driver of resistance to docetaxel via inhibition of GSDME-mediated proptosis and target this using a PJA1 inhibitor to restore sensitivity in preclinical models of NPC.

The identification of predictors for immunotherapy is often hampered by the absence of control groups in many studies, making it difficult to distinguish between prognostic and predictive biomarkers. This study presents biomarker analyses from the phase 3 CONTINUUM trial (NCT03700476), the first to show that adding anti-PD-1 (aPD1) to chemoradiotherapy (CRT) improves event-free survival (EFS) in patients with locoregionally advanced nasopharyngeal carcinoma. A dynamic single-cell atlas was profiled using mass cytometry on peripheral blood mononuclear cell samples from 12 pairs of matched relapsing and non-relapsing patients in the aPD1-CRT arm. Using a supervised representation learning algorithm, we identified a Ki67+ proliferating regulatory T cells (Tregs) population expressing high levels of activated and immunosuppressive molecules including FOXP3, CD38, HLA-DR, CD39, and PD-1, whose abundance correlated with treatment outcome. The frequency of these Ki67+ Tregs was significantly higher at baseline and increased during treatment in patients who relapsed compared to non-relapsers. Further validation through flow cytometry (n = 120) confirmed the predictive value of this Treg subset. Multiplex immunohistochemistry (n = 249) demonstrated that Ki67+ Tregs in tumors could predict immunotherapy benefit, with aPD1 improving EFS only in patients with low baseline levels of Ki67+ Tregs. These findings were further validated in the multicenter phase 3 DIPPER trial (n = 262, NCT03427827) and the phase 3 OAK trial of anti-PD-L1 immunotherapy in NSCLC, underscoring the predictive value of Ki67+ Treg frequency in identifying the beneficiaries of immunotherapy and potentially guiding personalized treatment strategies.

129 Background: Approximately 30% of locoregionally advanced nasopharyngeal carcinoma (NPC) experience disease relapse despite definitive chemoradiotherapy. The programmed death-1 (PD-1) blockade camrelizumab has demonstrated considerable value in recurrent/metastatic NPC, while its role in locoregionally advanced NPC is worth exploring. Methods: We conducted a randomized, open-label, phase 3 trial to evaluate adjuvant camrelizumab in locoregionally advanced NPC after definitive chemoradiotherapy. Patients with T4N1M0 or T1-4N2-3M0 NPC who have undergone induction chemotherapy and concurrent chemoradiotherapy were randomized in a 1:1 ratio to receive adjuvant camrelizumab (200mg intravenously once every 3 weeks for up to 12 cycles; Camrelizumab group) or observation ( Standard-therapy group). The primary endpoint was event-free survival (freedom from randomization to locoregional recurrence, distant metastasis, or death from any cause). The secondary endpoint included locoregional recurrence-free survival, distant metastasis-free survival, overall survival, safety, and quality of life. Results: A total of 226 patients were randomized to the Camrelizumab group and 224 to Standard-therapy group. At a median follow-up of 37 months, the 3-year event-free survival was 86.9% in the Camrelizumab group and 77.4% in the Standard-therapy groups (stratified hazard ratio, 0.61; 95% confidence interval [CI], 0.38 to 0.96; P = 0.03). Grade 3 or 4 adverse events were reported in 11.2% patients in the Camrelizumab group and 3.2% of those in the Standard-therapy group. The most common adverse event of grade 3 or 4 was leukopenia (4.9% and 1.4%, respectively). There was no meaningful deterioration in quality of life associated with the use of adjuvant camrelizumab. Conclusions: Adjuvant PD-1 blockade with camrelizumab significantly improved event-free survival, with mild toxicity, highlighting its compelling role in the management of locoregionally advanced NPC. (DIPPER,ClinicalTrials.gov numberNCT03427827). Clinical trial information: NCT03427827 . [Table: see text]

Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.

BACKGROUND:Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS:This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS:Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION:Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING:National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.