bims-meluca 2026-02-22 papers

Nature. 2026 Feb 18.

The integrated stress response promotes immune evasion through lipocalin 2.

Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.

DOI: https://doi.org/10.1038/s41586-026-10143-0

bioRxiv. 2025 Dec 03. pii: 2025.12.01.691597. [Epub ahead of print]

Tumor-Derived Polyamines Initiate Fat Wasting in Cancer Cachexia.

Matias Fabregat, Rachel J Fenske, Julia K Hansen, Cameron J Kaminsky, Jevin Lortie, Alexander Nassar, Kayla Kressin, Annie Jen, Lucia Cilloni, Katherine Overmeyer, Caroline M Alexander, John W Garrett, Perry J Pickhardt, Joshua J Coon, Costas A Lyssiotis, Marina Pasca di Magliano, Lingjun Li, Adam J Kuchnia, Andrea Galmozzi.

Cancer-associated cachexia (CC) is a fatal metabolic condition characterized by progressive loss of fat and muscle mass, yet its early molecular drivers remain poorly defined. Here, we identify a polyamine-dependent tumor-adipose crosstalk that triggers adipocyte lipolysis and fat wasting during the pre-cachexia stage, preceding systemic inflammation and muscle atrophy. Cancer-derived polyamines are enriched in extracellular vesicles and promote lipid mobilization via eIF5A hypusination, independent of adrenergic signaling. In preclinical models, polyamine accumulation associates with early fat loss and elevated circulating fatty acids. Clinically, automated CT imaging of newly diagnosed pancreatic cancer patients reveals increased adipose density, reflecting lipolysis, that correlates with circulating polyamine levels and predicts poor survival. These findings support polyamine metabolism as a mechanistic driver and candidate biomarker of early cachexia, providing a framework for early detection and targeted intervention.

DOI: https://doi.org/10.64898/2025.12.01.691597

Immunol Invest. 2026 Feb 16. 1-39

CD36-Mediated Fatty Acid Oxidation in CTCs Drives Immune Evasion and Metastasis in NSCLC.

Huizhen Zhu, Shuiyan Dai, Fengping Wang, Shuai Qian.

BACKGROUND: Immune checkpoint inhibitors (ICIs) show clinical benefit in subsets of non-small cell lung cancer (NSCLC) patients, yet resistance remains a major challenge. Circulating tumor cells (CTCs) contribute to tumor dissemination and immune regulation. This study investigated the metabolic features of CTC subpopulations under PD-1 resistance, with a focus on the role of CD36+CTCs in immune evasion and pre-metastatic niche (PMN) formation.
METHODS: PD-1-resistant in vitro and murine NSCLC models were established to enrich and isolate CTCs. CD36+ CTCs were characterized using lipid metabolomics, RNA sequencing, and functional assays. Their roles in PMN formation and immune suppression were evaluated using lung metastasis models and a tri-cell co-culture system. Fatty acid oxidation (FAO) dependency was assessed by lipid imaging, mitochondrial activity analysis, and pharmacological inhibition with etomoxir.
RESULTS: CD36+ CTCs were enriched under PD-1 resistance and exhibited enhanced lipid accumulation, increased mitochondrial activity, and FAO dependency. Multi-omics analyses revealed activation of lipid metabolic pathways associated with immune suppression and extracellular matrix remodeling. Functionally, CD36+ CTCs promoted PMN formation and inhibited T-cell activation, while FAO inhibition significantly reduced their migratory and metastatic potential.
CONCLUSION: CD36+ CTCs drive immune evasion and metastasis in PD-1-resistant NSCLC through FAO-dependent metabolic reprogramming. Targeting this metabolic vulnerability may enhance the efficacy of immunotherapy.

Keywords: CD36; Non-small cell lung cancer Model; circulating tumor cells; fatty acid oxidation; immune resistance; pre-metastatic niche

DOI: https://doi.org/10.1080/08820139.2026.2619575

J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70225

Cancer Cachexia Prevalence Is Underestimated in Medical Records of Patients in a Regional Tertiary Hospital.

Yann Colardelle, Melanie Daligault, Julien Grosjean, Stefan J Darmoni, Badisse Dahamna, Richard B Weiskopf, Vickie E Baracos.

BACKGROUND: Widespread lack of awareness and limited real-world prevalence evidence have impeded cachexia care and research. We hypothesized that healthcare professionals may identify the term cachexia, leading to International Classification of Diseases (ICD) coding for this term, with or without records of body weight loss for diagnosing cancer cachexia, and that frequently, ICD coding does not accurately reflect weight data.
METHODS: We assessed cachexia prevalence in patients diagnosed with cancer, using the Clinical Data Warehouse of a French hospital containing two types of real-world digitized data: (a) 'structured': coded diagnoses and electronic records; (b) 'unstructured': uncoded clinical narratives/reports: discharge summaries, procedure results, letters. Two sequential searches covering 2018-2023 (1) determined the prevalence of cachexia in all patients with a diagnosis of cancer using ICD-10 code R64 (cachexia), electronic records of body weight and unstructured narrative data; and (2) examined data of cancers of high-prevalence cachexia: colorectal, pancreatic and bronchial/lung cancers, determining (a) prevalence of cachexia by these criteria; (b) extent to which a diagnosis of cachexia was supported by weight loss data; and (c) extent to which the diagnosis of cachexia was not made despite objective weight data indicating its presence.
RESULTS: A total of 76 547 of 737 906 patients had cancer of any primary type; 1856 (2.42%) of these had a cachexia diagnosis: 620 identified by ICD code, 1507 by unstructured data, including 271 by both. Of 6946 patients with colorectal, pancreatic or bronchial/lung cancer, 2033 patients (29.3%) were identified with cachexia by structured and/or unstructured data; both approaches were required to discover cachexia cases. From structured data an ICD-R64 search found only 254 patients described by the term cachexia, of which 127 had weight data supporting the diagnosis in the electronic medical record. An additional 1340 patients with BMI < 20 kg/m2 or weight loss > 5% were not coded as cachectic. Unstructured data for the three cancers identified 439 additional cachexic patients.
CONCLUSIONS: (1) Standard ICD code-searching underestimated cachexia prevalence in all patients and those with high-prevalence-cachexia cancers; (2) Many cachexia cases were not diagnosed, although data indicated its presence; (3) Many cachexia cases diagnosed by judgement were not supported by data; (4) Increasing provider awareness of cancer cachexia definitions would likely improve cachexia care and research.

Keywords: ICD coding; cachexia; cancer; diagnosis; prevalence

DOI: https://doi.org/10.1002/jcsm.70225

Exp Hematol Oncol. 2026 Feb 16. 15(1): 28

Tumor-intrinsic PD-L1 drives lung cancer progression in response to TLR stimulation by promoting autophagy through the TRAF6-BECN1 signaling axis.

Yoolim Sung, Ha-Jeong Lee, Mi-Jeong Kim, Ji Hye Shin, Ji Young Kim, Yeeun Kang, Chaeeun Lee, Duk-Hwan Kim, Jae-Hyuck Shim, Tae Jin Kim, Eunyoung Chun, Ki-Young Lee.

BACKGROUND: Programmed death-ligand 1 (PD-L1, CD274) is well known for its immunosuppressive function within the tumor microenvironment; however, its tumor cell-intrinsic roles remain incompletely characterized. Emerging evidence suggests that PD-L1 may regulate oncogenic processes beyond immune evasion. This study aimed to define the intrinsic functions of PD-L1 in non-small cell lung cancer (NSCLC), with a focus on autophagy and metastasis-related signaling pathways.
METHODS: Integrated transcriptomic analyses of patient-derived NSCLC specimens were performed to evaluate associations between CD274 expression and oncogenic gene signatures. CRISPR-Cas9-mediated knockout and plasmid-driven overexpression of PD-L1 were conducted in H460 and A549 cell lines to assess proliferation, migration, clonogenicity, and 3D spheroid growth. Molecular interactions among PD-L1, TRAF6, and BECN1 were examined through immunoprecipitation and ubiquitination assays. Autophagy induction was evaluated by LC3 lipidation and autophagosome formation under Toll-like receptor (TLR) stimulation. The functional relevance of PD-L1 in metastasis was further assessed using xenograft models.
RESULTS: Clinical transcriptomic analyses demonstrated that CD274 upregulation correlates with enrichment of cancer progression, proliferation, and autophagy-associated gene sets in NSCLC. PD-L1 knockout markedly reduced cell proliferation, migration, clonogenicity, and 3D spheroid formation, whereas its overexpression enhanced these oncogenic phenotypes. Mechanistically, PD-L1 physically interacted with TRAF6 and BECN1, promoting TRAF6-dependent BECN1 ubiquitination and TLR-induced autophagy. PD-L1 depletion suppressed TLR-driven LC3 lipidation, autophagosome formation, and epithelial-mesenchymal transition (EMT), while PD-L1 overexpression augmented autophagy and EMT responses. In vivo, PD-L1-deficient lung cancer cells displayed diminished tumor growth and reduced metastatic potential in xenograft models.
CONCLUSIONS: This study identifies PD-L1 as a previously unrecognized intrinsic driver of NSCLC progression through activation of the TLR-TRAF6-BECN1 autophagy axis and promotion of EMT. Beyond its canonical role in immune evasion, PD-L1 functions as a dual-regulator of tumorigenesis by coordinating autophagy-dependent oncogenic processes. These findings provide novel mechanistic insight and support the therapeutic rationale for targeting PD-L1 not only as an immune checkpoint but also as a key modulator of cancer cell-intrinsic signaling in NSCLC.

Keywords: Autophagy; BECN1; Non-small cell lung cancer; Programmed death-ligand 1; TRAF6; Toll-like receptor

DOI: https://doi.org/10.1186/s40164-026-00761-9