Search Results (455)

Background and Clincal significance: Esophageal squamous cell carcinoma (ESCC) classically presents with progressive dysphagia and weight loss, but atypical presentations may redirect the diagnostic workup before the esophageal primary is identified. We report a case illustrating the simultaneous convergence of three diagnostic pitfalls: absence of dysphagia, bone-predominant metastatic presentation initially managed as carcinoma of unknown primary (CUP), and negative p40 staining in a vertebral biopsy in a patient subsequently confirmed to have invasive mid-esophageal squamous cell carcinoma. CasePresentation: A 66-year-old African American man with dementia, active tobacco exposure, and prior alcohol use disorder presented with constipation, abdominal pain, melena, fever, nausea, vomiting, and progressive back pain. Dysphagia or odynophagia was not documented. CT of the abdomen and pelvis demonstrated diffuse lytic osseous metastases. During evaluation and palliation of symptomatic L2 disease, kyphoplasty and radiofrequency ablation were performed, and bilateral core biopsies showed poorly differentiated carcinoma that was AE1/AE3-positive but negative for p40, CK7, CK20, TTF-1, S100, GATA-3, PAX8, and NKX3.1, yielding an initial diagnosis of CUP. Subsequent chest CT revealed esophageal wall thickening with intraluminal debris. Esophagogastroduodenoscopy (EGD) identified a non-obstructive ulcerated mid-esophageal lesion, and biopsy confirmed invasive squamous cell carcinoma. Poor performance status precluded systemic therapy; palliative external-beam radiation was initiated after diagnosis but discontinued because of clinical deterioration, and the patient transitioned to hospice before passing several weeks after diagnosis. Melena is a gastrointestinal alarm feature, and the combination of gastrointestinal bleeding and an esophageal imaging abnormality warrants timely endoscopic evaluation even when dysphagia is not reported or the symptom history is unreliable. Negative p40 staining in a poorly differentiated, potentially decalcified bone specimen may reflect loss of lineage-marker expression, technical antigen degradation, or both. Tissue or plasma genomic profiling and emerging cell-free DNA methylation classifiers could complement the workup but would not replace direct biopsy of a radiographically suspicious esophageal lesion. Conclusions: In metastatic poorly differentiated carcinoma, lack of documented dysphagia should not exclude an esophageal primary, particularly in patients with cognitive impairment. A p40-negative bone biopsy does not rule out squamous lineage. Timely EGD and integrated clinicopathologic assessment are essential when clinical or imaging findings suggest esophageal involvement. Full article

Background: Esophageal squamous cell carcinoma (ESCC) remains highly aggressive and continues to limit clinical treatment for substantial cancer-associated morbidity and mortality worldwide. Despite advances in therapeutic interventions the lack of effective molecularly targeted treatments continues to restrict clinical management beyond conventional chemotherapy and radiotherapy. Among these therapeutic targets the ribosomal S6 kinase 4 (RSK4) has gained considerable attention because of its critical involvement in ESCC progression, survival and proliferation, suggesting its potential as a potential target for anticancer drug development. Methods: A series of thiazole-clubbed pyrimidine linked hydrazone hybrids (1–14) were synthesized via 4-aminothiazole-5-carbohydrazide functionalized intermediates and fully characterized and evaluated for their inhibitory activity against RSK4. Results: Biological assessment demonstrated that the synthesized analogues exhibited remarkable potency, with IC₅₀ values between 15.32 ± 1.35 and 54.61 ± 2.17 nM compared with the reference inhibitor BI-D1870 (IC₅₀ = 33.16 ± 1.34 nM). Among the evaluated compounds, 2, 8, 9, 13 and 14 emerged as the most potent candidates and showed pronounced activity towards RSK4. For further insights into the molecular basis of their activity the lead candidates were subjected to computational investigations, such as molecular docking, molecular dynamics simulations, in silico ADMET and ProTox-3.0 characterization. The computational analyses provided structural and pharmacological insights into experimentally observed RSK4 inhibitory activity, like predicted interactions, stability dynamically and preliminary ADMET/toxicity characteristics. This study supports the need for further optimization and experimental validation of the identified RSK4 active lead candidates. Conclusions: These findings highlight the thiazole-clubbed pyrimidine-linked hydrazone scaffold as a potential chemotype for promising scaffolds targeting RSK4 lead discovery, and the identified candidates warrant further investigation into ESCC cellular models to establish anticancer efficacy and pathway-level activity. Full article

Reproducible high-performance computing pipelines for transcriptomic analysis are essential for population-scale precision oncology, yet most published workflows address only a single sequencing modality or lack benchmarking on underrepresented populations. We present KazRNA-Pipe, an open-source Nextflow v26.04.6 workflow processing both bulk and single-cell RNA sequencing (RNA-seq) within a unified Singularity-containerized environment with graphics processing unit (GPU) acceleration through the RAPIDS ecosystem. The pipeline was validated on 22 esophageal squamous cell carcinoma (ESCC) bulk RNA-seq samples from a Kazakhstan cohort (PRJNA608223) and on the largest public ESCC single-cell atlas (GSE160269). Quantification concordance across STAR, HISAT2, and Salmon reached Spearman ρ ≥ 0.90. BayesPrism deconvolution resolved cell-type proportions across all 22 samples. Full article

Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker for detecting minimal residual disease (MRD) and predicting recurrence after curative treatment, yet evidence in esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric cancer has largely been examined within individual tumor types. In this scoping review, we mapped this evidence across all three malignancies and clarified key methodological and clinical considerations. Following the PRISMA-ScR guidelines, we searched PubMed, Scopus, and the Cochrane Library (3 April 2026) for studies linking ctDNA to disease-free, recurrence-free, or overall survival after curative-intent treatment. Twenty-seven studies (1746 patients; 10 ESCC, 4 EAC, 8 gastric, and 5 mixed) were included. Across every tumor type, postoperative ctDNA MRD was the most informative timepoint, with independent multivariable hazard ratios for disease-free, recurrence-free, or event-free survival of 2.8 to 21.8, whereas preoperative ctDNA was seldom prognostic. Serial monitoring further improved performance and flagged recurrence 78 to 278 days before imaging. Tumor-informed assays showed higher sensitivity than tumor-agnostic ones (80% vs. 35%), though direct comparisons were limited; correction for clonal hematopoiesis was essential for tumor-agnostic assays, and blood-based assays performed poorly in diffuse-type and peritoneal disease. Postoperative ctDNA MRD is a consistent, independent prognostic biomarker across upper gastrointestinal cancers that adds prognostic information beyond conventional staging and pathological response, supporting prospective interventional trials of ctDNA-guided management. Full article

Background: Postoperative pneumonia (POP) is a critical complication after minimally invasive esophagectomy (MIE) for esophageal squamous cell carcinoma (ESCC). However, the comparative odds of POP among different neoadjuvant treatment strategies remain controversial. This study aimed to compare the associations between different treatment strategies and POP in this population. Methods: A retrospective cohort of ESCC patients undergoing MIE between March 2021 and July 2025 was analyzed. Patients were divided into four groups: the surgery alone (S-alone) group (n = 282), the neoadjuvant chemotherapy (NCT) group (n = 127), the neoadjuvant chemoradiotherapy (NCRT) group (n = 60), and the neoadjuvant chemoimmunotherapy (NCIT) group (n = 71). To address baseline confounding, generalized overlap weighting (GOW) was used for the four-group comparison, and overlap weighting (OW) was used for the pairwise comparisons of NCRT versus NCT and NCIT versus NCT. Logistic regression models were used to evaluate the associations between treatment strategies and the odds of POP. Sensitivity analyses of the pairwise comparisons were performed using stabilized inverse probability of treatment weighting (S-IPTW). Results: In the four-group comparison, neither NCT nor NCRT was associated with significantly higher odds of POP than S-alone, whereas NCIT was associated with higher odds (weighted odds ratio [OR], 1.95; 95% confidence interval [CI], 1.02–3.70). In pairwise analyses, the weighted ORs were 0.45 (95% CI, 0.20–1.01) for NCRT versus NCT and 2.32 (95% CI, 1.14–4.71) for NCIT versus NCT. Sensitivity analyses were directionally consistent. Conclusions: In this single-center observational cohort, NCRT was not associated with higher odds of POP than S-alone or NCT, whereas NCIT was associated with higher odds of POP. These findings support careful perioperative respiratory management in patients receiving neoadjuvant immunotherapy. Full article

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT–CD155–CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies. Full article

The African esophageal squamous cell carcinoma (ESCC) corridor extends from Ethiopia to the Eastern Cape and contains some of the highest age-standardized ESCC incidence rates reported anywhere, with five-year survival below 5%. The corridor’s heterogeneous incidence (sex ratios from 1:1 to 7:1; tenfold variation between adjacent populations) has resisted single-factor explanation through more than half a century of investigation. We synthesize the multicenter evidence accumulated since the IARC 2018 Group 2A classification of very hot beverages (>65 °C), with particular attention to the African Esophageal Cancer Consortium (ESCCAPE) outputs and to whole-genome sequencing. We argue, on the convergent evidence of animal toxicology, human in vitro mucosa, and population genomics, that thermal exposure acts as a tumor promoter rather than an initiator. On this reading, the corridor’s heterogeneous burden reflects heterogeneous chemical co-exposure profiles operating against a shared thermal-promoter substrate. Extending the comparative margin-of-exposure (MOE) methodology to esophageal squamous carcinogenesis, we present an MOE framework distinguishing genotoxic compounds (within-mode-of-action additive) from thermal exposure (separate companion figure) and apply it to two corridor scenarios. The framework supports a four-lever prevention strategy combining tobacco control, alcoholic-strength reduction in unrecorded spirits, clean-cookstove deployment, and graduated thermal-exposure reduction. Full article

Background: Squamous cell carcinomas (SCCs) share squamous differentiation and may engage the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway, although their causes, biology, and treatment differ by anatomical site. We evaluated tumor response, short-term survival, and grade 3–4 adverse events after neoadjuvant immune-checkpoint blockade, with or without chemotherapy, followed by surgery. Methods: A comprehensive search of PubMed, Embase, the Cochrane Library, and clinical trial registries was conducted from inception to October 2024. Prospective and retrospective studies evaluating neoadjuvant immunotherapy, with or without chemotherapy, before surgery in patients with SCC were included. In mixed-histology studies, data were eligible only when SCC outcomes could be extracted separately. Pooled proportions and 95% confidence intervals (CIs) were estimated with random-effects models. Results: A total of 44 studies involving 2586 patients with six anatomical SCC groups were included. The pooled objective response rate (ORR) was 0.70 (95% CI, 0.59–0.80), clinical complete response (cCR) rate was 0.17 (95% CI, 0.10–0.28), and pathological complete response (pCR) rate was 0.30 (95% CI, 0.27–0.34). The pooled 1-year progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS) rates were 0.82 (95% CI, 0.79–0.86), 0.86 (95% CI, 0.75–0.92), and 0.92 (95% CI, 0.90–0.93), respectively. The pooled incidence of grade 3–4 adverse events was 0.18 (95% CI, 0.14–0.23). Because the PD-L1 subgroup contained only one study for most outcomes, checkpoint-target subgroup findings were considered exploratory. Conclusions: Existing predominantly single-arm evidence suggests antitumor activity of neoadjuvant immune-checkpoint blockade, with or without chemotherapy, in selected patients with resectable SCC. Because esophageal SCC accounted for most studies and clinical heterogeneity was substantial, these pooled proportions should not be interpreted as comparative effects or as evidence of uniform benefit across SCC sites. Full article

Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with a poor prognosis, highlighting the urgent need to elucidate its molecular mechanisms to develop targeted therapies. Long non-coding RNAs (lncRNAs) play a critical role in cancer progression. However, the majority of lncRNAs involved in ESCC progression remain to be elucidated. Methods: We integrated bioinformatic analyses of the TCGA and GEO datasets to identify differentially expressed lncRNAs in ESCC, and the biological functions of the candidate lncRNA LINC01446 were investigated using loss-of-function assays in ESCC cell lines, including colony formation, wound healing, Transwell invasion, C11-BODIPY staining, malondialdehyde (MDA) quantification, and glutathione (GSH) evaluation. A nude mouse xenograft model was established for in vivo validation, and the underlying molecular mechanism was explored through RNA sequencing, fluorescence in situ hybridization (FISH), dual-luciferase reporter assays, AGO2-RIP, and rescue experiments. Results: LINC01446 was significantly upregulated in ESCC tissues and cell lines. Based on univariate analysis, high expression of LINC01446 was associated with poorer overall survival (OS). Functional studies showed that LINC01446 knockdown suppressed ESCC cell proliferation, migration, and invasion, promoted ferroptosis-related changes in vitro and was associated with increased lipid peroxidation and possible ferroptosis-related changes in vivo. Mechanistic analyses supported a regulatory relationship in which LINC01446 may function as a competing endogenous RNA (ceRNA) for miR-338-3p, thereby contributing to the upregulation of its downstream target, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1), in ESCC cells. Moreover, APEX1 was found to be overexpressed in ESCC and associated with poor OS. Conclusions: This study suggests that the LINC01446/miR-338-3p/APEX1 regulatory axis may contribute to ESCC progression and ferroptosis-related regulation. Additionally, LINC01446 and APEX1 represent promising prognostic biomarkers and therapeutic targets for ESCC. Full article

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent malignancy worldwide. Moreover, ESCC remains poorly characterized at the molecular level, which contributes to limited therapeutic options and an overall poor prognosis. In this context, HMGA family members, which are overexpressed in tumors but almost absent in healthy adult tissues, seem to represent promising therapeutic targets. These proteins act by binding to AT-hook DNA-binding motifs and may regulate the expression of several genes associated with tumor progression. Therefore, integrating in silico, translational, and in vitro approaches, we investigated the functional consequences of blocking HMGA2–DNA interaction in ESCC tumor progression by using netropsin, a site-specific ligand for AT-rich DNA regions. Our results demonstrate that netropsin treatment significantly reduced cell viability, migration, and cell cycle progression, thereby promoting apoptosis. Furthermore, netropsin treatment was capable of partially reverting Epithelial–Mesenchymal Transition (EMT) activation associated with HMGA2 expression, by downregulating EMT activators, such as Slug and Twist. Finally, the netropsin treatment sensitizes ESCC cells to chemotherapeutic treatment with 5-Fluorouracil. Taken together, our findings highlight that AT binding-specific blockade could be correlated with the inhibition of HMGA2 and may reveal a promising approach to better understand ESCC progression. Full article

Background/Objectives: Hepatoid adenocarcinoma is a rare adenocarcinoma subtype. Synchronous esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma with hepatoid differentiation is exceptionally uncommon. This report describes lesion-specific staging, pathological response assessment, and individualized management after neoadjuvant chemoimmunotherapy. Methods: De-identified clinical, imaging, laboratory, operative, and pathological data were retrospectively reviewed. Both lesions were staged according to the AJCC 8th edition and reassessed using the CAP modified Ryan four-tier tumor regression grading system. Results: A 61-year-old man presenting with dysphagia had separate ESCC and gastric cardia adenocarcinoma, both staged cT2N0M0. One cycle of pembrolizumab 200 mg, nab-paclitaxel 300 mg, and cisplatin 100 mg was administered. Agranulocytosis precluded further neoadjuvant therapy; after neutrophil recovery, R0 resection was performed. Pathological review showed ESCC ypT1aN0M0, score 1, and cardia adenocarcinoma ypT1aN0M0, score 3, with approximately 30% regional hepatoid differentiation. All 10 examined lymph nodes were negative. AFP was not measured before treatment; post-treatment/preoperative values were 14.45 and 14.68 ng/mL, and the postoperative value was 6.08 ng/mL. Postoperative tislelizumab monotherapy was selected as an individualized, non-standard strategy, mainly because of affordability. At approximately 6 months after surgery, no recurrence, metastasis, or maintenance-related adverse event was identified. Conclusions: This case emphasizes biopsy under-sampling and lesion-specific staging and pathological assessment. The regression-score difference is descriptive and confounded by baseline burden, histology, and one-cycle exposure; the AFP findings do not validate a surveillance biomarker. Full article

Chimeric antigen receptor (CAR)-T therapy has achieved partial therapeutic efficacy in solid tumors, but its overall effectiveness remains limited. IL-21-armored CD276.CAR-T (IL21.CD276.CAR-T) represents a promising strategy to enhance anti-tumor activity against esophageal squamous cell carcinoma (ESCC). However, resistance mechanisms remain unclear. We generated IL21.CD276.CAR-T cells and evaluated their cytotoxicity in vitro and in B-NDG xenograft models. Poliovirus receptor (PVR) expression on ESCC cells was analyzed, and shRNA-mediated PVR knockdown was performed to validate its role in resistance. IL-21R expression on ESCC cells was examined to exclude direct IL-21 signaling. IL-21 enhances the cytotoxicity of CD276.CAR-T cells against ESCC. Although IL21.CD276.CAR-T exhibited potent cytotoxicity in vitro, it failed to achieve complete tumor regression, and resistant cells still emerged. Mechanistically, resistance was not caused by CD276 antigen loss or IL-21R expression, but by upregulation of PVR on cancer cell membrane after IL21.CAR-T exposure. PVR knockdown restored CAR-T sensitivity in vitro, enhanced the anti-tumor capacity of IL21.CD276.CAR-T cells, and partially improved anti-tumor efficacy in vivo without systemic toxicity. PVR may act as a mediator of resistance to IL21.CD276.CAR-T in ESCC. Targeting PVR represents a novel strategy to overcome IL21.CAR-T resistance and improve therapeutic outcomes in ESCC. Full article

Esophageal squamous-cell carcinoma (ESCC) remains a highly lethal malignancy, with long-term survival still unsatisfactory and an urgent need for clinically relevant molecular targets. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an RNA-binding protein with oncogenic activity in several tumor types, but the signaling events associated with its role in ESCC have not been fully defined. IGF2BP2 expression was examined in paired ESCC and adjacent non-tumor tissues by immunohistochemistry (10 paired samples) and qRT-PCR (16 paired samples). Associations with clinicopathological variables were evaluated in 108 TCGA ESCC cases. Stable lentiviral shRNA-mediated knockdown was established in KYSE30 and ECA109 cells. CCK-8, colony formation, Transwell, EdU, and flow cytometry assays were used to assess proliferation, clonogenic growth, migration, invasion, apoptosis, and cell-cycle distribution. EMT-associated markers were measured by Western blotting and qRT-PCR. RNA sequencing, KEGG enrichment analysis, and rescue experiments using the AKT activator SC79 were performed to explore downstream signaling. IGF2BP2 was upregulated in ESCC tissues at both the transcript and protein levels, and higher expression was associated with unfavorable clinicopathological characteristics. Silencing IGF2BP2 reduced proliferation, colony formation, migration, and invasion, promoted G0/G1 cell-cycle arrest, and increased apoptosis. EMT-associated marker analysis showed decreased Snail and increased Slug expression, indicating that these changes require cautious interpretation. RNA sequencing and KEGG analysis suggested enrichment of PI3K/AKT-related signaling after IGF2BP2 knockdown. IGF2BP2 silencing decreased PI3K and p-PI3K levels, whereas SC79 partly restored migratory and invasive capacities. IGF2BP2 contributes to malignant phenotypes in ESCC and may be associated with PI3K/AKT-related signaling. These findings indicate that IGF2BP2 is a candidate biomarker and potential therapeutic target, although further mechanistic and pharmacologic validation is required. Full article

Nimotuzumab is a humanized anti-EGFR monoclonal antibody with a unique pharmacodynamic profile characterized by intermediate affinity and bivalent binding dependence, enabling density-selective tumor targeting while sparing normal tissues from the severe skin rash and other toxicities common to EGFR inhibitors. Since its first approval in 2002, nimotuzumab has been registered for eight cancer indications. Unlike conventional fixed-dose schedules, emerging evidence supports prolonged administration beyond initial combination therapy. This review summarizes clinical data from pancreatic cancer, esophageal cancer, high-grade glioma, pediatric diffuse intrinsic pontine glioma, head and neck squamous cell carcinoma, nasopharyngeal cancer and other solid tumors, showing that extended nimotuzumab exposure, often as maintenance monotherapy, may prolong overall survival, progression-free survival, and disease control compared to limited cycles. Despite heterogeneity in tumor types and treatment regimens, maintenance nimotuzumab was consistently associated with better results, particularly in terms of overall survival. Notably, significant survival benefits were observed in locally advanced SCCHN (24.9 vs. 12.5 months) and esophageal cancer (15.9 vs. 8.1 months) across independent clinical trials. Mechanistically, nimotuzumab exerts direct cytostatic effects via G1 arrest, potent anti-angiogenic activity through VEGF downregulation, indirect pro-apoptotic effects, and broad immunomodulation including ADCC, NK-DC cross-talk, EGFR-specific CD8+ T cell priming, upregulation of HLA class I, and favorable regulation of regulatory T cells. Its density-selective binding reduces selective pressure for acquired resistance. Future research priorities should include prospective randomized trials specifically evaluating maintenance strategies, biomarker-driven patient selection, the molecular characterization of resistance mechanisms, integration with immunotherapy and modern combination regimens, and the development of next-generation platforms, including antibody–drug conjugates and multi-specific constructs. Full article

While altered lipid metabolism is a hallmark of cancer, specific phospholipid dependencies remain poorly defined. Here, we identify phosphatidylserine synthase 1 (PTDSS1) as a targetable metabolic vulnerability in esophageal squamous cell carcinoma (ESCC) and glioblastoma (GBM). Pharmacological inhibition of PTDSS1 selectively and potently suppresses tumor growth both in vitro and in vivo. Mechanistically, PTDSS1 blockade triggers a rapid collapse of cellular phosphatidylserine (PS) and phosphatidylethanolamine (PE) pools, fundamentally disrupting endoplasmic reticulum (ER) homeostasis. This targeted lipid depletion activates a PERK-mediated autophagic response that ultimately yields to apoptosis. Clinically, pan-cancer transcriptomic analysis links elevated PTDSS1 expression to reduced overall survival across diverse malignancies. Collectively, we establish PTDSS1 as an essential maintainer of ER integrity and highlight PS biosynthesis as a viable therapeutic target for exploiting tumor-specific metabolic dependencies. Full article