Lung cancer (LC) is a leading cause of cancer-related deaths worldwide. Its rapid growth requires hyperactive catabolism of principal metabolic fuels. It is unclear whether fructose, an abundant sugar in current diets, is essential for LC. We demonstrated that, under the condition of coexistence of metabolic fuels in the body, fructose was readily used by LC cells in vivo as a glucose alternative via upregulating GLUT5, a major fructose transporter encoded by solute carrier family 2 member 5 ( SLC2A5 ). Metabolomic profiling coupled with isotope tracing demonstrated that incorporated fructose was catabolized to fuel fatty acid synthesis and palmitoleic acid generation in particular to expedite LC growth in vivo. Both in vitro and in vivo supplement of palmitoleic acid could restore impaired LC propagation caused by SLC2A5 deletion. Furthermore, molecular mechanism investigation revealed that GLUT5-mediated fructose utilization was required to suppress AMPK and consequently activate mTORC1 activity to promote LC growth. As such, pharmacological blockade of in vivo fructose utilization using a GLUT5 inhibitor remarkably curtailed LC growth. Together, this study underscores the importance of in vivo fructose utilization mediated by GLUT5 in governing LC growth and highlights a promising strategy to treat LC by targeting GLUT5 to eliminate those fructose-addicted neoplastic cells.

Esophageal squamous cell carcinoma (ESCC) is a major histological subtype of esophageal cancer with inferior prognosis. Here, we conducted comprehensive transcriptomic, proteomic, phosphoproteomic, and metabolomic characterization of human, treatment‐naive ESCC and paired normal adjacent tissues (cohort 1, n = 24) in an effort to identify new molecular vulnerabilities for ESCC and potential therapeutic targets. Integrative analysis revealed a small group of genes that were related to the active posttranscriptional and posttranslational regulation of ESCC. By using proteomic, phosphoproteomic, and metabolomic data, networks of ESCC‐related signaling and metabolic pathways that were closely linked to cancer etiology were unraveled. Notably, integrative analysis of proteomic and phosphoproteomic data pinpointed that certain pathways involved in RNA transcription, processing, and metabolism were stimulated in ESCC. Importantly, proteins with close linkage to ESCC prognosis were identified. By enrolling an ESCC patient cohort 2 (n = 41), three top‐ranked prognostic proteins X‐prolyl aminopeptidase 3 (XPNPEP3), bromodomain PHD finger transcription factor (BPTF), and fibrillarin (FBL) were verified to have increased expression in ESCC. Among these prognostic proteins, only FBL, a well‐known nucleolar methyltransferase, was essential for ESCC cell growth in vitro and in vivo. Furthermore, a validation study using an ESCC patient cohort 3 (n = 100) demonstrated that high FBL expression predicted unfavorable patient survival. Finally, common cancer/testis antigens and established cancer drivers and kinases, all of which could direct therapeutic decisions, were characterized. Collectively, our multi‐omics analyses delineated new molecular features associated with ESCC pathobiology involving epigenetic, posttranscriptional, posttranslational, and metabolic characteristics, and unveiled new molecular vulnerabilities with therapeutic potential for ESCC.

Esophageal squamous cell carcinoma (ESCC) is a major histological subtype of esophageal cancer with a poor prognosis. Although several serum metabolomic investigations have been reported, ESCC tumor-associated metabolic alterations and predictive biomarkers in sera have not been defined. Here, we enrolled 34 treatment-naive patients with ESCC and collected their pre- and post-esophagectomy sera together with the sera from 34 healthy volunteers for a metabolomic survey. Our comprehensive analysis identified ESCC tumor-associated metabolic alterations as represented by a panel of 12 serum metabolites. Notably, postoperative abrosia and parenteral nutrition substantially perturbed the serum metabolome. Furthermore, we performed an examination using sera from carcinogen-induced mice at the dysplasia and ESCC stages and identified three ESCC tumor-associated metabolites conserved between mice and humans. Notably, among these metabolites, the level of pipecolic acid was observed to be progressively increased in mouse sera from dysplasia to cancerization, and it could be used to accurately discriminate between mice at the dysplasia stage and healthy control mice. Furthermore, this metabolite is essential for ESCC cells to restrain oxidative stress-induced DNA damage and cell proliferation arrest. Together, this study revealed a panel of 12 ESCC tumor-associated serum metabolites with potential for monitoring therapeutic efficacy and disease relapse, presented evidence for refining parenteral nutrition composition, and highlighted serum pipecolic acid as an attractive biomarker for predicting ESCC tumorigenesis.

The importance of fibrillarin (FBL), an established nucleolar methyltransferase, was identified in neoplastic growth of esophageal squamous cell carcinoma (ESCC), one of the most lethal malignancies worldwide. However, the underlying mechanism remains unclear. Here, by enrolling independent ESCC cohorts, we verified the negative correlation between intratumoral FBL expression and patient prognosis. Notably, comprehensive transcriptomic and metabolomic analyses indicated that FBL deletion elicited cell cycle arrest and cellular senescence, as well as block of nicotinamide metabolism and increase of oxidative stress. Mechanistically, FBL could bind to and stabilize SIRT1 by obstructing the ubiquitin‐proteasome‐mediated protein degradation, therefore provoking nicotinamide metabolism, sustaining redox homeostasis, and counteracting senescence. Clinically, FBL‐SIRT1 axis was augmented in tumor tissues of ESCC patients, and high intratumoral SIRT1 expression predicted poor patient survival. Finally, we found that both genetic and pharmacological inhibition of FBL could sensitize senolytic therapy for ESCC. In conclusion, we first discovered FBL as an anti‐senescent protein in tumor progression. FBL resists cellular senescence by stabilizing SIRT1 and sustaining the nicotinamide metabolism, therefore providing an optional strategy for ESCC treatment by sensitizing senolytic therapy with FBL inhibitors.

In small cell lung cancer (SCLC), immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy are standard first-line treatment for extensive-stage disease. However, durable disease control remains uncommon. This review examines lineage plasticity, epigenetic regulation, defective antigen presentation, and altered DNA sensing and interferon responses. These processes interact with T-cell dysfunction, suppressive myeloid populations, and organ-specific niches. Treatment-associated clonal and cell-state changes complicate the distinction between chemotherapy resistance and immune escape. We relate these processes to primary and acquired resistance and assess interventions according to treatment setting and evidence source. Randomized SCLC trials support selected maintenance and first-line combination regimens and delta-like ligand 3 (DLL3)-directed T-cell redirection. By contrast, evidence for epigenetic, innate-immune, and myeloid targeting remains largely preclinical. Findings from non-small cell lung cancer (NSCLC) and other tumors provide indirect evidence that cannot be extrapolated directly to SCLC. Emerging lineage vulnerabilities and traditional Chinese medicine remain exploratory. We discuss the overlap between chemotherapy and immunotherapy resistance, opportunities and constraints arising from plasticity, and the validation needed for mechanism-informed interventions.