---
title: "PDLIM2 in Lung Adenocarcinoma: Prognostic Biomarker and Therapeutic Candidate"
id: "british-journal-of-cancer-0-exploring-pdlim2-as-a-prognostic-biomarker-and-therapeutic-target-in-lung"
canonical_url: "https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-exploring-pdlim2-as-a-prognostic-biomarker-and-therapeutic-target-in-lung"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "British Journal of Cancer"
source_url: "https://www.nature.com/articles/s41416-026-03570-3"
published_at: "2026-08-08T12:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# PDLIM2 in Lung Adenocarcinoma: Prognostic Biomarker and Therapeutic Candidate
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-exploring-pdlim2-as-a-prognostic-biomarker-and-therapeutic-target-in-lung
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** British Journal of Cancer
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41416-026-03570-3)
- **Published At:** 2026-08-08T12:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The study evaluated **PDLIM2** expression and therapeutic potential in lung adenocarcinoma (LUAD) using next-generation sequencing, immunohistochemistry, and preclinical gene therapy. - Analysis included LUAD tissues from 15,765 patients; PDLIM2-high tumors were more frequent in primary/local biopsies than in metastatic samples (73.1% vs 53.0%; p < 0.001). - High **PDLIM2** expression correlated with lower mutation rates in RB1, TP53, SMARCA4, STK11, and KEAP1, and with increased frequency of EGFR mutations (all p < 0.01). - PDLIM2-high tumors showed increased immune cell infiltration, higher T cell–inflamed scores, and greater PD-L1 positivity (all p < 0.008), consistent with an immune-receptive tumor microenvironment. - Clinically, high PDLIM2 was associated with longer overall survival (24.1 vs 18.1 months; p < 0.001; HR = 0.84) and remained an independent prognostic factor in multivariate analysis (HR = 0.88, 95% CI 0.83–0.93). - High PDLIM2 also associated with longer duration on pembrolizumab, notably when combined with platinum-based chemotherapy (p = 0.012, HR = 0.867). - Preclinical testing delivered exogenous PDLIM2 via intravenous nano-complexed plasmid DNA (nanoPDLIM2) in two syngeneic LUAD mouse models; nanoPDLIM2 plus chemoimmunotherapy improved median overall survival versus chemoimmunotherapy alone (10–12.5 vs 8–9 days; N = 8; p = 0.0001, 0.0003). - PDLIM2 exerts tumor-suppressive effects through negative regulation of NF-κB and STAT3 signaling, and restoration of PDLIM2 enhances sensitivity to chemotherapy and immunotherapy in preclinical models. - The authors conclude **PDLIM2** is a promising prognostic biomarker linked to immune-receptive LUAD and that PDLIM2-based therapy potentiates chemoimmunotherapy in mice; the predictive role for treatment response requires further clinical evaluation.
## Clinical Analysis & Structured Key Points
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[nature](https://www.nature.com/) 2. [british journal of cancer](https://www.nature.com/bjc) 3. [articles](https://www.nature.com/bjc/articles?type=article) 4. article Exploring _PDLIM2_ as a prognostic biomarker and therapeutic target in lung adenocarcinoma [ Download PDF ](https://www.nature.com/articles/s41416-026-03570-3.pdf) [ Download PDF ](https://www.nature.com/articles/s41416-026-03570-3.pdf) * Article * [Open access](https://www.springernature.com/gp/open-science/about/the-fundamentals-of-open-access-and-open-research) * Published: 08 August 2026 Translational Therapeutics # Exploring _PDLIM2_ as a prognostic biomarker and therapeutic target in lung adenocarcinoma * [Karam Ashouri](https://www.nature.com/articles/s41416-026-03570-3#auth-Karam-Ashouri-Aff1) [ORCID: orcid.org/0009-0000-1825-1033](https://orcid.org/0009-0000-1825-1033)[1](https://www.nature.com/articles/s41416-026-03570-3#Aff1), * [Fan Sun](https://www.nature.com/articles/s41416-026-03570-3#auth-Fan-Sun-Aff2)[2](https://www.nature.com/articles/s41416-026-03570-3#Aff2), * [Harris Krause](https://www.nature.com/articles/s41416-026-03570-3#auth-Harris-Krause-Aff3)[3](https://www.nature.com/articles/s41416-026-03570-3#Aff3), * [Andrew Elliott](https://www.nature.com/articles/s41416-026-03570-3#auth-Andrew-Elliott-Aff3) [ORCID: orcid.org/0000-0001-8494-8031](https://orcid.org/0000-0001-8494-8031)[3](https://www.nature.com/articles/s41416-026-03570-3#Aff3), * [Stephen V. Liu](https://www.nature.com/articles/s41416-026-03570-3#auth-Stephen_V_-Liu-Aff4)[4](https://www.nature.com/articles/s41416-026-03570-3#Aff4), * [Patrick C. Ma](https://www.nature.com/articles/s41416-026-03570-3#auth-Patrick_C_-Ma-Aff5)[5](https://www.nature.com/articles/s41416-026-03570-3#Aff5), * [Balazs Halmos](https://www.nature.com/articles/s41416-026-03570-3#auth-Balazs-Halmos-Aff6) [ORCID: orcid.org/0000-0001-7548-8360](https://orcid.org/0000-0001-7548-8360)[6](https://www.nature.com/articles/s41416-026-03570-3#Aff6), * [Gutian Xiao](https://www.nature.com/articles/s41416-026-03570-3#auth-Gutian-Xiao-Aff1-Aff7-Aff8)[1](https://www.nature.com/articles/s41416-026-03570-3#Aff1),[7](https://www.nature.com/articles/s41416-026-03570-3#Aff7),[8](https://www.nature.com/articles/s41416-026-03570-3#Aff8), * [Ari Vanderwalde](https://www.nature.com/articles/s41416-026-03570-3#auth-Ari-Vanderwalde-Aff3)[3](https://www.nature.com/articles/s41416-026-03570-3#Aff3), * [Jorge J. Nieva](https://www.nature.com/articles/s41416-026-03570-3#auth-Jorge_J_-Nieva-Aff1) [ORCID: orcid.org/0000-0003-1605-4719](https://orcid.org/0000-0003-1605-4719)[1](https://www.nature.com/articles/s41416-026-03570-3#Aff1) & * … * [Zhaoxia Qu](https://www.nature.com/articles/s41416-026-03570-3#auth-Zhaoxia-Qu-Aff1-Aff7-Aff8) [ORCID: orcid.org/0000-0002-2769-9814](https://orcid.org/0000-0002-2769-9814)[1](https://www.nature.com/articles/s41416-026-03570-3#Aff1),[7](https://www.nature.com/articles/s41416-026-03570-3#Aff7),[8](https://www.nature.com/articles/s41416-026-03570-3#Aff8) Show authors [_British Journal of Cancer_](https://www.nature.com/bjc) (2026) [Cite this article](https://www.nature.com/articles/s41416-026-03570-3#citeas) [ Save article ](https://www.nature.com/articles/s41416-026-03570-3/save-research?_csrf=72EuzAzbg5HHtIHXBEEACuHUcCCAKt9H) [ View saved research ](https://www.nature.com/saved-research) ## Abstract ### Background While PDZ-LIM domain-containing protein (PDLIM2) suppresses lung cancer, its clinical significance and therapeutic potential remain to be fully explored. ### Methods Next-generation sequencing and immunohistochemistry of programmed death ligand 1 (PD-L1) were performed on lung adenocarcinoma (LUAD) tissues from 15,765 patients. _PDLIM2_ gene therapy was tested in syngeneic LUAD mouse models using intravenous nano-complexed plasmid DNA, alone or with chemoimmunotherapy. ### Results _PDLIM2_ -high tumors were more common in primary/local biopsies versus metastatic samples (73.1% vs 53.0%; _p_ < 0.001). High _PDLIM2_ expression was linked to lower mutation rates in _RB1_ , _TP53_ , _SMARCA4, STK11_ , and _KEAP1_ , but increased _EGFR_ mutations (all _p_ < 0.01). _PDLIM2_ -high tumors also showed increased immune cell infiltration, T cell-inflamed scores, and PD-L1 positivity (all _p_ < 0.008). High _PDLIM2_ was associated with improved survival (24.1 vs 18.1 months; _p_ < 0.001, HR = 0.84) and remained prognostic in multivariate analysis (HR = 0.88, 95% CI 0.83–0.93), as well as with longer pembrolizumab time, especially with platinum-based therapy (_p_ = 0.012, HR = 0.867). In two LUAD mouse models, nanoPDLIM2 improved median overall survival versus chemoimmunotherapy alone (10–12.5 vs 8–9 days; N = 8; _p_ = 0.0001, 0.0003). ### Conclusion _PDLIM2_ is a promising prognostic biomarker in LUAD linked to immune-receptive tumors. Preclinically, _PDLIM2_ -based therapy enhances chemoimmunotherapy efficacy, though its predictive role warrants further evaluation. ## Introduction Lung cancer remains the leading cause of cancer-related deaths among both men and women in the U.S. with a 5-year survival rate of only 27% [[1](https://www.nature.com/articles/s41416-026-03570-3#ref-CR1 "Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75:10–45.")]. Blockade of the interaction between the immune checkpoint PD-1 (also known as CD279) and PD-L1 (also known as B7-H1 or CD274) using PD-1 or PD-L1 antibodies is now part of the standard treatment for advanced _EGFR_ /_ALK_ wild type non-small cell lung cancer [[2](https://www.nature.com/articles/s41416-026-03570-3#ref-CR2 "Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–61."),[3](https://www.nature.com/articles/s41416-026-03570-3#ref-CR3 "Bardhan K, Anagnostou T, Boussiotis VA. The PD1:PD-L1/2 pathway from discovery to clinical implementation. Front Immunol. 2016;7:550."),[4](https://www.nature.com/articles/s41416-026-03570-3#ref-CR4 "Malhotra J, Jabbour SK, Aisner J. Current state of immunotherapy for non-small cell lung cancer. Transl Lung Cancer Res. 2017;6:196–211.")]. Given the synergy demonstrated in preclinical and clinical trials, chemoimmunotherapy is an established treatment option that combines immunotherapy with traditional chemotherapy [[5](https://www.nature.com/articles/s41416-026-03570-3#ref-CR5 "Sun F, Li L, Yan P, Zhou J, Shapiro SD, Xiao G, et al. Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance. Nat Commun. 2019;10:5324."),[6](https://www.nature.com/articles/s41416-026-03570-3#ref-CR6 "Sun F, Yan P, Xiao Y, Zhang H, Shapiro SD, Xiao G, et al. Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2. Elife. 2024;12."),[7](https://www.nature.com/articles/s41416-026-03570-3#ref-CR7 "Sun F, Guo ZS, Gregory AD, Shapiro SD, Xiao G, Qu Z. Dual but not single PD-1 or TIM-3 blockade enhances oncolytic virotherapy in refractory lung cancer. J Immunother Cancer. 2020;8."),[8](https://www.nature.com/articles/s41416-026-03570-3#ref-CR8 "Leonetti A, Wever B, Mazzaschi G, Assaraf YG, Rolfo C, Quaini F, et al. Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer. Drug Resist Updat. 2019;46:100644."),[9](https://www.nature.com/articles/s41416-026-03570-3#ref-CR9 "Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, et al. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer \(KEYNOTE-189\): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:387–97.")]. Tumor PD-L1 expression is the most commonly used biomarker of ICI response; however, its predictive value in lung cancer is poor [[10](https://www.nature.com/articles/s41416-026-03570-3#ref-CR10 "Yamaguchi H, Hsu JM, Sun L, Wang SC, Hung MC. Advances and prospects of biomarkers for immune checkpoint inhibitors. Cell Rep Med. 2024;5:101621.")]. Therefore, it is essential to identify additional biomarkers for ICI response, understand the mechanisms underlying ICI resistance in lung adenocarcinoma (LUAD), and explore new combination therapies to improve treatment outcomes. _PDLIM2_ is a tumor suppressor implicated in the pathogenesis of various cancers [[5](https://www.nature.com/articles/s41416-026-03570-3#ref-CR5 "Sun F, Li L, Yan P, Zhou J, Shapiro SD, Xiao G, et al. Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance. Nat Commun. 2019;10:5324."), [6](https://www.nature.com/articles/s41416-026-03570-3#ref-CR6 "Sun F, Yan P, Xiao Y, Zhang H, Shapiro SD, Xiao G, et al. Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2. Elife. 2024;12."), [11](https://www.nature.com/articles/s41416-026-03570-3#ref-CR11 "Sun F, Xiao Y, Qu Z. Oncovirus Kaposi sarcoma herpesvirus \(KSHV\) represses tumor suppressor PDLIM2 to persistently activate nuclear factor κB \(NF-κB\) and STAT3 transcription factors for tumorigenesis and tumor maintenance. J Biol Chem. 2015;290:7362–8."),[12](https://www.nature.com/articles/s41416-026-03570-3#ref-CR12 "Qu Z, Yan P, Fu J, Jiang J, Grusby MJ, Smithgall TE, et al. DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target. Cancer Res. 2010;70:1766–72."),[13](https://www.nature.com/articles/s41416-026-03570-3#ref-CR13 "Qu Z, Fu J, Yan P, Hu J, Cheng SY, Xiao G. Epigenetic repression of PDZ-LIM domain-containing protein 2: implications for the biology and treatment of breast cancer. J Biol Chem. 2010;285:11786–92."),[14](https://www.nature.com/articles/s41416-026-03570-3#ref-CR14 "Yan P, Fu J, Qu Z, Li S, Tanaka T, Grusby MJ, et al. PDLIM2 suppresses human T-cell leukemia virus type I Tax-mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation. Blood. 2009;113:4370–80."),[15](https://www.nature.com/articles/s41416-026-03570-3#ref-CR15 "Yan P, Qu Z, Ishikawa C, Mori N, Xiao G. Human T-cell leukemia virus type I-mediated repression of PDZ-LIM domain-containing protein 2 involves DNA methylation but independent of the viral oncoprotein tax. Neoplasia. 2009;11:1036–41."),[16](https://www.nature.com/articles/s41416-026-03570-3#ref-CR16 "Fu J, Yan P, Li S, Qu Z, Xiao G. Molecular determinants of PDLIM2 in suppressing HTLV-I Tax-mediated tumorigenesis. Oncogene. 2010;29:6499–507."),[17](https://www.nature.com/articles/s41416-026-03570-3#ref-CR17 "Vanoirbeek E, Eelen G, Verlinden L, Carmeliet G, Mathieu C, Bouillon R, et al. PDLIM2 expression is driven by vitamin D and is involved in the pro-adhesion, and anti-migration and -invasion activity of vitamin D. Oncogene. 2014;33:1904–11."),[18](https://www.nature.com/articles/s41416-026-03570-3#ref-CR18 "Guo ZS, Qu Z. PDLIM2: Signaling pathways and functions in cancer suppression and host immunity. Biochim Biophys Acta Rev Cancer. 2021;1876:188630.")]. In non-small cell lung cancer (NSCLC) including LUAD, _PDLIM2_ expression is frequently reduced, and this reduction is associated with poor clinical outcomes [[5](https://www.nature.com/articles/s41416-026-03570-3#ref-CR5 "Sun F, Li L, Yan P, Zhou J, Shapiro SD, Xiao G, et al. Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance. Nat Commun. 2019;10:5324."), [6](https://www.nature.com/articles/s41416-026-03570-3#ref-CR6 "Sun F, Yan P, Xiao Y, Zhang H, Shapiro SD, Xiao G, et al. Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2. Elife. 2024;12.")]. Functionally, PDLIM2 has been shown to suppress tumor cell growth, migration, and invasion in both in vitro and in vivo models [[5](https://www.nature.com/articles/s41416-026-03570-3#ref-CR5 "Sun F, Li L, Yan P, Zhou J, Shapiro SD, Xiao G, et al. Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance. Nat Commun. 2019;10:5324."), [6](https://www.nature.com/articles/s41416-026-03570-3#ref-CR6 "Sun F, Yan P, Xiao Y, Zhang H, Shapiro SD, Xiao G, et al. Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2. Elife. 2024;12.")]. Furthermore, _PDLIM2_ restoration by nano-delivery of exogenous _PDLIM2_ (nanoPDLIM2) or pharmacological induction of endogenous _PDLIM2_ enhances the sensitivity of chemotherapy and immunotherapy in a mouse model of primary LUAD [[5](https://www.nature.com/articles/s41416-026-03570-3#ref-CR5 "Sun F, Li L, Yan P, Zhou J, Shapiro SD, Xiao G, et al. Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance. Nat Commun. 2019;10:5324."), [6](https://www.nature.com/articles/s41416-026-03570-3#ref-CR6 "Sun F, Yan P, Xiao Y, Zhang H, Shapiro SD, Xiao G, et al. Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2. Elife. 2024;12.")]. The tumor-suppressive effects of _PDLIM2_ are mediated through multiple mechanisms [[18](https://www.nature.com/articles/s41416-026-03570-3#ref-CR18 "Guo ZS, Qu Z. PDLIM2: Signaling pathways and functions in cancer suppression and host immunity. Biochim Biophys Acta Rev Cancer. 2021;1876:188630.")]. One key mechanism involves the negative regulation of the NF-κB and STAT3 signaling pathways [[5](https://www.nature.com/articles/s41416-026-03570-3#ref-CR5 "Sun F, Li L, Yan P, Zhou J, Shapiro SD, Xiao G, et al. Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic resistance. Nat Commun. 2019;10:5324."), [6](https://www.nature.com/articles/s41416-026-03570-3#ref-CR6 "Sun F, Yan P, Xiao Y, Zhang H, Shapiro SD, Xiao G, et al. Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2. Elife. 2024;12."), [11](https://www.nature.com/articles/s41416-026-03570-3#ref-CR11 "Sun F, Xiao Y, Qu Z. Oncovirus Kaposi sarcoma herpesvirus \(KSHV\) represses tumor suppressor PDLIM2 to persistently activate nuclear factor κB \(NF-κB\) and STAT3 transcription factors for tumorigenesis and tumor maintenance. J Biol Chem. 2015;290:7362–8."),[12](https://www.nature.com/articles/s41416-026-03570-3#ref-CR12 "Qu Z, Yan P, Fu J, Jiang J, Grusby MJ, Smithgall TE, et al. DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target. Cancer Res. 2010;70:1766–72."),[13](https://www.nature.com/articles/s41416-026-03570-3#ref-CR13 "Qu Z, Fu J, Yan P, Hu J, Cheng SY, Xiao G. Epigenetic repression of PDZ-LIM domain-containing protein 2: implications for the biology and treatment of breast cancer. J Biol Chem. 2010;285:11786–92."), [19](https://www.nature.com/articles/s41416-026-03570-3#ref-CR19 "Tanaka T, Grusby MJ, Kaisho T. PDLIM2-mediated termination of transcription factor NF-kappaB activation by intranuclear sequestration and degradation of the p65 subunit. Nat Immunol. 2007;8:584–91."), [20](https://www.nature.com/articles/s41416-026-03570-3#ref-CR20 "Qu Z, Fu J, Ma H, Zhou J, Jin M, Mapara MY, et al. PDLIM2 restricts Th1 and Th17 differentiation and prevents autoimmune disease. Cell Biosci. 2012;2:23.")]. NF-κB and STAT3 are two master transcription factors that play a central role in inflammation, metabolic reprogramming, cell survival, and tumorigenesis [[21](https://www.nature.com/articles/s41416-026-03570-3#ref-CR21 "Xiao G, Fu J. NF-κB and cancer: a paradigm of Yin-Yang. Am J Cancer Res. 2011;1:192–221."),[22](https://www.nature.com/articles/s41416-026-03570-3#ref-CR22 "Xiao G, Rabson AB, Young W, Qing G, Qu Z. Alternative pathways of NF-kappaB activation: a double-edged sword in health and disease. Cytokine Growth Factor Rev. 2006;17:281–93."),[23](https://www.nature.com/articles/s41416-026-03570-3#ref-CR23 "Li L, Han L, Sun F, Zhou J, Ohaegbulam KC, Tang X, et al. NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8. Oncoimmunology. 2018;7:e1435250."),[24](https://www.nature.com/articles/s41416-026-03570-3#ref-CR24 "Li L, Han L, Qu Z. NF-κB RelA is a cell-intrinsic metabolic checkpoint restricting glycolysis. Cell Biosci. 2024;14:11."),[25](https://www.nature.com/articles/s41416-026-03570-3#ref-CR25 "Qing G, Qu Z, Xiao G. Endoproteolytic processing of C-terminally truncated NF-kappaB2 precursors at kappaB-containing promoters. Proc Natl Acad Sci USA. 2007;104:5324–9."),[26](https://www.nature.com/articles/s41416-026-03570-3#ref-CR26 "Zhou J, Qu Z, Sun F, Han L, Li L, Yan S, et al. Myeloid STAT3 promotes lung tumorigenesis by transforming tumor immunosurveillance into tumor-promoti
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