{
  "abstract": "BackgroundImmune checkpoint blockade has reshaped lung cancer treatment, yet durable benefit remains restricted to a subset of patients. Biomarkers incompletely capture interactions between immune activation and tumor-intrinsic resistance. Integrating immune and epithelial expression programs may help identify response-associated states and candidates for functional investigation.MethodsPublic bulk transcriptomes were analyzed with format-specific preprocessing, empirical Bayes differential expression, standardized cross-cohort evidence, and gene-set enrichment. Five discovery-informed modules formed an immune-resistance score. Conditional leave-one-out and leave-cohort-out analyses refitted normalization within training data and compared the fixed score with a nested ridge-logistic model. Survival, composition-adjustment, and prioritization sensitivity analyses were performed. Single-cell counts underwent quality control, unsupervised clustering, and patient-level pseudobulk analysis. MAL2 was investigated in A549 and H1299 cells using knockdown, growth, motility, apoptosis, HLA-ABC, cytokine, and PBMC co-culture assays.ResultsNo individual gene met FDR <0.05 in any of the three discovery contrasts. Favorable-response genes were enriched for adaptive immune processes, whereas the unfavorable list showed weaker DNA-replication enrichment. Conditional leave-cohort-out AUCs for the dual-axis score were 0.964, 0.859, and 0.773; performance did not consistently exceed the immune axis. In GSE190266, outcome analysis yielded a cohort-relative AUC of 0.617 with incomplete module coverage. Higher scores were associated with longer PFS in two evaluated cohorts. Quality control retained 91,762 single cells. MAL2 remained epithelial-enriched and ranked third among 58 evaluable candidates, but its patient-level epithelial response contrast and standalone PFS associations were not significant. Knockdown reduced growth and motility-related readouts, increased apoptosis and HLA-ABC expression, and altered cytokine and co-culture activation readouts.ConclusionThe immune-resistance framework links cohort-level response patterns to epithelial candidates for functional investigation. MAL2 depletion alters growth and immune-related phenotypes in lung cancer cells, supporting further investigation of its biological role.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "Original Research",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "JingYi Zhang"
    },
    {
      "name": "Siqi Luo"
    },
    {
      "name": "Xinming Jing"
    },
    {
      "name": "Xianfeng Lu"
    },
    {
      "name": "Yanli Xiong"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8b6zambhe68gw.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1940144",
  "fulltext_url": null,
  "id": "8b6zambhe68gw",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1940144",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "feed-journal",
      "medicine/pharmacology-toxicology"
    ]
  ],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-30",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/8b6zambhe68gw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:21Z",
      "native_id": "10.3389/fphar.2026.1940144",
      "source": "feed-frontiers",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1940144"
    },
    {
      "first_seen": "2026-10-30T12:20:08Z",
      "native_id": "10.3389/fphar.2026.1940144",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1940144/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "feed-journal:medicine/pharmacology-toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "An immune-resistance dual-axis framework prioritizes MAL2 for functional investigation in lung cancer",
  "title_text": "An immune-resistance dual-axis framework prioritizes MAL2 for functional investigation in lung cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T00:21:04Z",
  "url": "https://research.draconitic.com/paper/8b6zambhe68gw",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}