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Lung Carcinoma

Disease Pathophysiology Research Report

2026-01-31
Falcon MONDO:0005138 Model: Edison Scientific Literature 44 citations

Disease Pathophysiology Research Report

Target Disease - Disease Name: Lung Carcinoma - MONDO ID: MONDO:0008903 - Category: Cancer

Pathophysiology Description (current understanding) Lung carcinoma encompasses non-small-cell lung cancer (NSCLC, ~85% of cases) and small-cell lung cancer (SCLC, ~15%). NSCLC is dominated by adenocarcinoma and squamous cell carcinoma; SCLC is a neuroendocrine carcinoma with high proliferative capacity and early metastasis (5-year OS typically <10% in extensive stage) (May 2024; Nature Communications, https://doi.org/10.1038/s41467-024-48700-8; Oct 2024; Nature Reviews Clinical Oncology, https://doi.org/10.1038/s41571-024-00914-x) (zuani2024singlecellandspatial pages 1-2, sen2024emergingadvancesin pages 1-3). Globally in 2022, lung cancer accounted for 2.48 million new cases and 1.82 million deaths (GLOBOCAN 2022, updated 8 Feb 2024; https://gco.iarc.fr/today) (hendriks2024nonsmallcelllungcancer. pages 1-2).

Oncogenic drivers and signaling. NSCLC pathogenesis is driven by recurrent activating alterations in EGFR, KRAS, ALK, ROS1, BRAF, MET, and others, typically in a mutually exclusive fashion in adenocarcinoma; LUSC harbors frequent TP53 inactivation and copy gains (e.g., FGFR1), while LUAD shows TP53 inactivation in ~50% (narrative review summarizing genomics and risk) (Mar 2023; Annals of Translational Medicine, https://doi.org/10.21037/atm-22-4479) (ibodeng2023asnapshotof pages 4-5). SCLC, by contrast, almost universally has biallelic loss of TP53 (~92%) and RB1 (~74–95%) and is tightly linked to tobacco-associated mutational signatures (Oct 2024; Trends in Cancer, https://doi.org/10.1016/j.trecan.2024.07.008) (redin2024smallcelllung pages 1-3). Dysregulated pathways downstream include RAS–RAF–MEK–ERK (MAPK), PI3K–AKT–mTOR, NOTCH, and HIPPO/YAP–TAZ, with crosstalk to interferon/STING and antigen-presentation pathways that shape immune surveillance and response to immunotherapy (Mar 2024; Cancer Gene Therapy, https://doi.org/10.1038/s41417-024-00761-z; Dec 2024; Translational Lung Cancer Research, https://doi.org/10.21037/tlcr-24-662) (liang2024hippopathwayin pages 1-2, schneider2024fuelforthought pages 2-4).

Tumor microenvironment (TME) and immune evasion. Single-cell and spatial profiling in treatment-naive NSCLC reveals a myeloid-dominant TME with macrophage reprogramming toward cholesterol export and a fetal-like signature promoting iron efflux, inversely related to NK/T-cell cytotoxicity; checkpoints are co-expressed in subtype-specific patterns (May 2024; Nature Communications, https://doi.org/10.1038/s41467-024-48700-8) (zuani2024singlecellandspatial pages 1-2). After neoadjuvant chemoimmunotherapy, responders showed enrichment of SELENOP+ macrophages and antigen-presenting CAFs co-localized at tumor boundaries and within tertiary lymphoid structures, with increased interactions with CD4+/CD8+ T cells—features linked to sensitivity (Apr 2025; Molecular Cancer, https://doi.org/10.1186/s12943-025-02287-w) (cui2025singlecellandspatial pages 1-3). In SCLC, a T-cell–inflamed (SCLC-I) subset exhibits higher MHC gene signatures and derives greater benefit from chemoimmunotherapy; in CASPIAN, overall survival with D±T+EP was numerically highest in the SCLC-inflamed subtype (“median 24.0 months”) and high CD8A/MHC signatures associated with improved outcomes (May 2024; Molecular Cancer, https://doi.org/10.1186/s12943-024-02014-x) (xie2024molecularclassificationand pages 1-2).

Metabolic reprogramming. Lung cancers exhibit genotype- and histology-linked metabolic states: squamous tumors are highly glycolytic with GLUT1/MCT1 elevation, whereas adenocarcinomas vary in FDG avidity; KRAS-mutant NSCLC often shows glutamine dependence and flexible glycolysis–OXPHOS coupling; KEAP1–NFE2L2 axis mutations drive antioxidant/redox adaptations and treatment resistance (Dec 2024; Translational Lung Cancer Research, https://doi.org/10.21037/tlcr-24-662) (schneider2024fuelforthought pages 2-4). A 2024 review details the spectrum beyond the Warburg effect to lipid and amino-acid metabolism as clinical targets (Dec 2024; Frontiers in Pharmacology, https://doi.org/10.3389/fphar.2024.1516650) (huang2024metabolicreprogrammingin pages 1-2).

Epigenetic alterations. Progressive DNA methylation changes and chromosomal instability cooperate across LUAD precursors and invasive tumors, with telomere shortening in precancers and increasing immune checkpoint upregulation—implicating epigenome–genome cooperation in early carcinogenesis and immune evasion (May 2024; Research Square preprint, https://doi.org/10.21203/rs.3.rs-4396272/v1) (zhang2024theevolutionof pages 1-6). Epigenetic regulators (e.g., histone methyltransferases, EZH2) and DNMTs contribute to drug tolerance and immunotherapy resistance by altering chromatin state and antigen presentation programs in both tumor and stromal cells (2024–2025 reviews) (sen2024emergingadvancesin pages 1-3, zhang2024theevolutionof pages 1-6).

Lineage plasticity and histologic transformation. SCLC comprises dynamic transcriptional cell states defined by lineage factors ASCL1 (A), NEUROD1 (N), POU2F3 (P), with an inflamed (I) subtype; intratumoral heterogeneity and state shifts under therapy drive resistance (Oct 2024; Trends in Cancer, https://doi.org/10.1016/j.trecan.2024.07.008) (redin2024smallcelllung pages 9-11, redin2024smallcelllung pages 1-3). NSCLC can transform to SCLC as an acquired resistance mechanism to targeted therapy or, less commonly, immunotherapy; clinical series highlight enrichment for TP53/RB1 alterations in transforming cases (Oct 2023; Frontiers in Immunology, https://doi.org/10.3389/fimmu.2023.1275957) (das2025recentadvancesin pages 6-7).

Evolution from premalignant lesions. LUAD evolves along a spectrum from atypical adenomatous hyperplasia (AAH) → adenocarcinoma in situ (AIS) → minimally invasive (MIA) → invasive adenocarcinoma (IAC). Multi-omics across 213 lesions show increasing mutations, chromosomal aberrations, whole-genome doubling, and stemness, alongside a shift from innate immune dominance to adaptive recruitment with rising immune checkpoints in later stages (May 2024; Research Square, https://doi.org/10.21203/rs.3.rs-4396272/v1) (zhang2024theevolutionof pages 1-6).

Embedded summary table of mechanisms and evidence | Mechanistic area | NSCLC / SCLC focus | Principal genes / proteins (HGNC) | Dysregulated pathways (GO terms where applicable) | Tumor microenvironment features (cell subsets, CL) | Metabolic programs (CHEBI metabolites) | Epigenetics | Lineage plasticity / Transformation | Premalignant evolution | Representative recent sources | |---|---|---|---|---|---|---|---|---|---| | Oncogenic drivers & signaling | • NSCLC: EGFR, KRAS, ALK, ROS1, BRAF, MET; targeted therapy relevance. (brockley2025inferringpersistentmolecular pages 17-22)
• SCLC: TP53 & RB1 loss, high TMB, smoking-associated. (redin2024smallcelllung pages 1-3) | EGFR, KRAS, ALK, ROS1, BRAF, MET, TP53, RB1, STK11, KEAP1. (brockley2025inferringpersistentmolecular pages 17-22, redin2024smallcelllung pages 1-3) | MAPK cascade (GO:0000165); PI3K-AKT (GO:0008286); Hippo/YAP-TAZ (GO:0035329); NOTCH (GO:0007219); cGAS–STING / Type I IFN. (brockley2025inferringpersistentmolecular pages 17-22, liang2024hippopathwayin pages 1-2, schneider2024fuelforthought pages 2-4) | Oncogene-driven PD-L1 upregulation; impaired antigen presentation; stromal/CAF remodeling. (yadav2024themirnaand pages 1-2, zuani2024singlecellandspatial pages 1-2) | Warburg glycolysis vs OXPHOS balance; KRAS-linked glutamine dependence; KEAP1–NFE2L2 redox adaptation. (schneider2024fuelforthought pages 2-4, huang2024metabolicreprogrammingin pages 1-2) | DNA methylation cooperates with genomic alterations; histone modifier dysregulation modulates driver expression/resistance. (zhang2024theevolutionof pages 1-6, sen2024emergingadvancesin pages 1-3) | EGFR‑mutant LUAD can transform to SCLC under therapy; RB1/TP53 alterations link to neuroendocrine switch. (das2025recentadvancesin pages 6-7, sen2024emergingadvancesin pages 1-3) | Progressive accumulation of drivers and chromosomal instability during AAH → AIS → MIA → IAC; immune context shifts. (zhang2024theevolutionof pages 1-6, brockley2025inferringpersistentmolecular pages 17-22) | (brockley2025inferringpersistentmolecular pages 17-22, redin2024smallcelllung pages 1-3, liang2024hippopathwayin pages 1-2) | | Tumor microenvironment & immune evasion | • NSCLC: heterogeneous inflamed vs immune-excluded regions; CAF–macrophage niches modulate response. (zuani2024singlecellandspatial pages 1-2, cui2025singlecellandspatial pages 1-3)
• SCLC: inflamed (I) vs neuroendocrine (A/N/P) subtypes with variable infiltration. (redin2024smallcelllung pages 1-3, xie2024molecularclassificationand pages 1-2) | PDCD1 (PD-1), CD274 (PD-L1), exosomal PD-L1, SPP1, FAP, SELENOP. (yadav2024themirnaand pages 1-2, cui2025singlecellandspatial pages 1-3, zuani2024singlecellandspatial pages 1-2) | Antigen processing/presentation (GO:0019882); IFN-γ signaling (GO:0060333); chemokine-mediated recruitment dysregulated. (xie2024molecularclassificationand pages 1-2, cui2025singlecellandspatial pages 1-3) | SPP1+ and SELENOP+ macrophages, CXCL9+ and TREM2+ TAMs, FAP+ CAFs, Tregs, exhausted CD8+ T cells, tertiary lymphoid structures in responders. (cui2025singlecellandspatial pages 1-3, zuani2024singlecellandspatial pages 1-2, xie2024molecularclassificationand pages 1-2) | Cholesterol/lipid handling by TAMs, lactate-mediated T-cell suppression, tumor–CAF metabolic coupling. (zuani2024singlecellandspatial pages 1-2, schneider2024fuelforthought pages 2-4) | Epigenetic reprogramming in CAFs and myeloid cells alters cytokine and antigen-presentation programs, impacting ICI response. (sen2024emergingadvancesin pages 1-3, cui2025singlecellandspatial pages 1-3) | TME remodeling accompanies histologic shifts and alters ICI sensitivity. (das2025recentadvancesin pages 6-7, xie2024molecularclassificationand pages 1-2) | Early lesions show immune niche transitions (loss of innate cells, recruitment of adaptive effectors, checkpoint upregulation). (zhang2024theevolutionof pages 1-6) | (cui2025singlecellandspatial pages 1-3, zuani2024singlecellandspatial pages 1-2, xie2024molecularclassificationand pages 1-2) | | Metabolic reprogramming | • NSCLC: genotype-linked metabolic phenotypes (KRAS→glycolysis/glutamine; EGFR/ALK effects). (schneider2024fuelforthought pages 2-4, huang2024metabolicreprogrammingin pages 1-2)
• SCLC: subtype-specific nucleotide/GTP or lipid liabilities. (redin2024smallcelllung pages 1-3) | SLC2A1 (GLUT1), SCD1, GLS, KEAP1, NFE2L2. (schneider2024fuelforthought pages 2-4, huang2024metabolicreprogrammingin pages 1-2) | Glycolysis (GO:0006096); oxidative phosphorylation (GO:0006119); glutamine catabolism (GO:0006541) reprogrammed. (huang2024metabolicreprogrammingin pages 1-2) | Metabolic competition (glucose/lactate) limits T-cell function; myeloid lipid programs suppress immunity. (schneider2024fuelforthought pages 2-4, zuani2024singlecellandspatial pages 1-2) | Key metabolites: glucose (CHEBI:17234), lactate (CHEBI:24996), glutamine (CHEBI:25052), fatty acids/PUFAs. (schneider2024fuelforthought pages 2-4) | Metabolism–epigenome crosstalk (SAM, acetyl-CoA) alters chromatin and influences therapy response. (zhang2024theevolutionof pages 1-6, huang2024metabolicreprogrammingin pages 1-2) | Metabolic shifts (glycolysis↔OXPHOS) support EMT/stemness and facilitate lineage switching/resistance. (schneider2024fuelforthought pages 2-4, das2025recentadvancesin pages 6-7) | Early metabolic/mitochondrial stress signatures in precursors predict progression risk. (zhang2024theevolutionof pages 1-6, huang2024metabolicreprogrammingin pages 1-2) | (schneider2024fuelforthought pages 2-4, huang2024metabolicreprogrammingin pages 1-2, redin2024smallcelllung pages 1-3) | | Epigenetic alterations & therapy resistance | • NSCLC/SCLC: DNA hypermethylation of tumor suppressors and deregulated histone modifiers drive heterogeneity and resistance. (zhang2024theevolutionof pages 1-6, sen2024emergingadvancesin pages 1-3) | DNMT1, EZH2 and other HMTs/HDACs implicated in chromatin rewiring and drug tolerance. (sen2024emergingadvancesin pages 1-3, zhang2024theevolutionof pages 1-6) | Chromatin modification (GO:0016568); epigenetic regulation of transcription (GO:0040029) broadly dysregulated. (zhang2024theevolutionof pages 1-6) | Epigenetic remodeling in CAFs/myeloid cells modifies cytokine profiles and antigen presentation, affecting ICI outcomes. (cui2025singlecellandspatial pages 1-3, sen2024emergingadvancesin pages 1-3) | One‑carbon metabolism (SAM), acetyl‑CoA pools influence methylation/acetylation states. (zhang2024theevolutionof pages 1-6) | Circulating DNA methylation signatures are emerging biomarkers; HMTs linked to drug tolerance. (zhang2024theevolutionof pages 1-6, sen2024emergingadvancesin pages 1-3) | Epigenetic plasticity enables dedifferentiation and activation of neuroendocrine programs (NSCLC→SCLC). (das2025recentadvancesin pages 6-7, sen2024emergingadvancesin pages 1-3) | Progressive epigenomic instability parallels CIN and immune escape in precursors. (zhang2024theevolutionof pages 1-6) | (zhang2024theevolutionof pages 1-6, sen2024emergingadvancesin pages 1-3) | | Lineage plasticity & SCLC subtypes | • Therapy-induced transdifferentiation (e.g., EGFR LUAD→SCLC) fuels resistance. (das2025recentadvancesin pages 6-7)
• SCLC transcriptional subtypes: ASCL1 (A), NEUROD1 (N), POU2F3 (P), inflamed (I), YAP1-related. (redin2024smallcelllung pages 1-3) | ASCL1, NEUROD1, POU2F3, MYC, TP53, RB1. (redin2024smallcelllung pages 1-3, sen2024emergingadvancesin pages 1-3) | Notch (GO:0007219) and Hippo/YAP-TAZ (GO:0035329) regulate lineage/differentiation; chromatin regulators permit switches. (liang2024hippopathwayin pages 1-2, zhang2024theevolutionof pages 1-6) | Subtype-linked immune contexts: SCLC-I (inflamed, higher MHC/PD-L1) vs SCLC-A/N (immune-cold). (xie2024molecularclassificationand pages 1-2, sen2024emergingadvancesin pages 1-3) | Subtype-associated nucleotide and lipid metabolic dependencies (e.g., MYC-driven). (schneider2024fuelforthought pages 2-4, redin2024smallcelllung pages 1-3) | Chromatin/epigenetic remodeling underlies transdifferentiation; epigenetic therapies under study. (sen2024emergingadvancesin pages 1-3, zhang2024theevolutionof pages 1-6) | Reported transformation frequency variable (~10–20% post‑targeted therapy); often under-recognized without re-biopsy. (sen2024emergingadvancesin pages 1-3, das2025recentadvancesin pages 6-7) | Certain premalignant archetypes may predispose to aggressive or transformation-prone invasive tumors. (zhang2024theevolutionof pages 1-6) | (redin2024smallcelllung pages 1-3, das2025recentadvancesin pages 6-7, sen2024emergingadvancesin pages 1-3) | | Premalignant progression (AAH → AIS → MIA → IAC) | • LUAD precursor cascade with stage-dependent molecular and immune changes; opportunity for interception. (zhang2024theevolutionof pages 1-6, brockley2025inferringpersistentmolecular pages 17-22) | Early driver events: EGFR, KRAS; increasing chromosomal instability and telomere shortening. (zhang2024theevolutionof pages 1-6) | Genome instability, DNA repair dysregulation, and activation of immune-evasion programs accompany progression. (zhang2024theevolutionof pages 1-6) | Shift from innate immunity (macrophage-dominated) to adaptive recruitment (T/B cells), with checkpoint upregulation and spatial niche changes. (zhang2024theevolutionof pages 1-6, cui2025singlecellandspatial pages 1-3) | Mitochondrial dsRNA–associated stress and metabolic shifts mark precancer stages. (zhang2024theevolutionof pages 1-6, huang2024metabolicreprogrammingin pages 1-2) | Early DNA methylation changes define progression trajectories; circulating methylation biomarkers show promise. (zhang2024theevolutionof pages 1-6) | Premalignant archetype heterogeneity (proliferation vs normal-like) predicts invasive phenotype and prognosis. (zhang2024theevolutionof pages 1-6) | Clinical sequence AAH→AIS→MIA→IAC with measurable molecular hallmarks at each step. (zhang2024theevolutionof pages 1-6, brockley2025inferringpersistentmolecular pages 17-22) | (zhang2024theevolutionof pages 1-6, brockley2025inferringpersistentmolecular pages 17-22, cui2025singlecellandspatial pages 1-3) |

Table: Compact, evidence‑linked summary table of major molecular, cellular, metabolic and epigenetic mechanisms in NSCLC and SCLC, with connections to TME, lineage plasticity and premalignant progression (cited to context IDs).

Recent developments and latest research (priority 2023–2024) - NSCLC single-cell/spatial TME atlas (Nature Communications 2024): Defined macrophage reprogramming and checkpoint co-expression differences between LUAD and LUSC; inverse relation of anti-inflammatory macrophages with NK/T-cell cytotoxicity (May 2024; https://doi.org/10.1038/s41467-024-48700-8) (zuani2024singlecellandspatial pages 1-2). - SCLC molecular/therapeutic landscape (NRCO 2024; Trends in Cancer 2024): Consolidated ASCL1/NEUROD1/POU2F3 subtypes and an inflamed class; plasticity under therapy and emerging DLL3-based agents (Jul 2024; https://doi.org/10.1038/s41571-024-00914-x; Oct 2024; https://doi.org/10.1016/j.trecan.2024.07.008) (sen2024emergingadvancesin pages 1-3, redin2024smallcelllung pages 1-3). - Biomarkers for immunotherapy in SCLC (CASPIAN 2024): CD8A cell density, MHC I/II/APM signatures associate with superior OS on durvalumab±tremelimumab plus EP; PD-L1 and TMB alone did not robustly stratify outcomes (May 2024; https://doi.org/10.1186/s12943-024-02014-x) (xie2024molecularclassificationand pages 1-2). - Hippo/YAP–TAZ in NSCLC resistance (2024): Mechanistic synthesis linking YAP/TAZ-TEAD to proliferation, EMT, stemness, immune evasion, and drug resistance; outlines therapeutic targeting strategies (Mar 2024; https://doi.org/10.1038/s41417-024-00761-z) (liang2024hippopathwayin pages 1-2). - Metabolism in lung cancer (2024): Review of genotype-specific metabolic phenotypes, KEAP1–NFE2L2 axis, and clinical targeting of glycolysis, glutamine and lipid pathways (Dec 2024; https://doi.org/10.21037/tlcr-24-662; Dec 2024; https://doi.org/10.3389/fphar.2024.1516650) (schneider2024fuelforthought pages 2-4, huang2024metabolicreprogrammingin pages 1-2). - LUAD precursors multi-omics (2024): Chromosomal instability, telomere attrition, increased stemness, and adaptive immune shift with checkpoint upregulation across AAH→AIS→MIA→IAC (May 2024; https://doi.org/10.21203/rs.3.rs-4396272/v1) (zhang2024theevolutionof pages 1-6). - miRNA–PD-1/PD-L1 axis (2024): miRNA programs modulate ICI sensitivity and T-cell exhaustion, suggesting combinatorial epigenetic–immune strategies (Sep 2024; Cell Death Discovery, https://doi.org/10.1038/s41420-024-02182-1) (yadav2024themirnaand pages 1-2).

Current applications and real-world implementations - Immunotherapy in SCLC: Durvalumab + EP is first-line standard; TME immunologic signatures (CD8A, MHC I/II/APM) can enrich for benefit and may guide biomarker-driven selection (May 2024; Mol Cancer; https://doi.org/10.1186/s12943-024-02014-x) (xie2024molecularclassificationand pages 1-2). - Targeted therapy in NSCLC: Genotype-directed inhibitors for EGFR, ALK, ROS1, BRAF, MET; pathway cross-talk (e.g., YAP–TAZ activation) contributes to resistance and motivates trials of TEAD inhibitors and combination regimens (Mar 2024; Cancer Gene Therapy; https://doi.org/10.1038/s41417-024-00761-z) (liang2024hippopathwayin pages 1-2). - TME-guided strategies: Spatial single-cell studies propose leveraging SELENOP+ macrophage–apCAF niches and tertiary lymphoid structures as biomarkers of chemoimmunotherapy responsiveness in resectable NSCLC (Apr 2025; Mol Cancer; https://doi.org/10.1186/s12943-025-02287-w) (cui2025singlecellandspatial pages 1-3). - Metabolic targeting: KEAP1–NFE2L2 mutant tumors and KRAS/STK11 co-mutant subsets show distinct metabolic vulnerabilities, informing clinical trials of glutaminase, lipid metabolism, and redox modulators (Dec 2024; TLCR; https://doi.org/10.21037/tlcr-24-662) (schneider2024fuelforthought pages 2-4).

Expert opinions and analysis (authoritative sources) - “SCLC comprises distinct transcriptional cell states driven by lineage-defining factors (ASCL1, NEUROD1, POU2F3)… an inflammatory phenotype occurs across subtypes…and intratumoral heterogeneity and plasticity are key resistance drivers.” (Oct 2024; Trends in Cancer; https://doi.org/10.1016/j.trecan.2024.07.008) (redin2024smallcelllung pages 9-11, redin2024smallcelllung pages 1-3). - “OS with D±T+EP was numerically highest in the SCLC-inflamed subtype (median 24.0 months)… OS benefit … was associated with high expression of CD4 and antigen-presenting and processing machinery and with higher MHC I expression.” (May 2024; Molecular Cancer; https://doi.org/10.1186/s12943-024-02014-x) (xie2024molecularclassificationand pages 1-2). - “Tumor-associated macrophages adopt a cholesterol-exporting, fetal-like transcriptional signature… inversely associated with NK/T-cell cytotoxicity.” (May 2024; Nature Communications; https://doi.org/10.1038/s41467-024-48700-8) (zuani2024singlecellandspatial pages 1-2). - “YAP/TAZ nuclear translocation promotes proliferation, EMT, stemness, immune evasion, and drug resistance in NSCLC.” (Mar 2024; Cancer Gene Therapy; https://doi.org/10.1038/s41417-024-00761-z) (liang2024hippopathwayin pages 1-2).

Relevant statistics and data from recent studies - Global burden (2022): 2,480,675 incident lung cancer cases; 1,817,469 deaths (GLOBOCAN 2022; updated Feb 2024; https://gco.iarc.fr/today) (hendriks2024nonsmallcelllungcancer. pages 1-2). - Histology split: NSCLC ~85%, SCLC ~15% (May 2024; Nature Communications; https://doi.org/10.1038/s41467-024-48700-8) (zuani2024singlecellandspatial pages 1-2). - CASPIAN SCLC biomarker analysis: SCLC-inflamed subtype median OS 24.0 months on D±T+EP; CD8A-high/MHC-high signatures associated with greater OS benefit (May 2024; https://doi.org/10.1186/s12943-024-02014-x) (xie2024molecularclassificationand pages 1-2).

Required Information 1) Core Pathophysiology - Primary mechanisms: Oncogenic driver activation (EGFR, KRAS, ALK, ROS1, BRAF, MET), tumor suppressor loss (TP53, RB1), pathway dysregulation (MAPK, PI3K/AKT/mTOR, HIPPO/YAP–TAZ, NOTCH), TME-mediated immune evasion (PD-1/PD-L1 axis, antigen presentation defects), metabolic reprogramming (glycolysis/OXPHOS, glutamine/lipid metabolism), epigenetic remodeling, and lineage plasticity (NSCLC↔SCLC, adeno↔squamous) (2024–2025 sources as above) (liang2024hippopathwayin pages 1-2, zuani2024singlecellandspatial pages 1-2, schneider2024fuelforthought pages 2-4, redin2024smallcelllung pages 1-3, xie2024molecularclassificationand pages 1-2, zhang2024theevolutionof pages 1-6, yadav2024themirnaand pages 1-2). - Dysregulated pathways: MAPK cascade; PI3K–AKT–mTOR; Hippo/YAP–TAZ; NOTCH; IFN/cGAS–STING signaling relating to immunogenicity (Mar 2024, Dec 2024) (liang2024hippopathwayin pages 1-2, schneider2024fuelforthought pages 2-4). - Cellular processes: Proliferation, EMT, stemness, antigen processing/presentation, macrophage polarization and metabolic rewiring (May 2024, Mar 2024) (zuani2024singlecellandspatial pages 1-2, liang2024hippopathwayin pages 1-2).

2) Key Molecular Players - Genes/Proteins (HGNC): EGFR, KRAS, ALK, ROS1, BRAF, MET, TP53, RB1, STK11, KEAP1; PDCD1 (PD-1), CD274 (PD-L1); ASCL1, NEUROD1, POU2F3; YAP1 (YAP), WWTR1 (TAZ) (ibodeng2023asnapshotof pages 4-5, redin2024smallcelllung pages 1-3, liang2024hippopathwayin pages 1-2, xie2024molecularclassificationand pages 1-2, zuani2024singlecellandspatial pages 1-2). - Chemical Entities (CHEBI): glucose (CHEBI:17234), lactate (CHEBI:24996), glutamine (CHEBI:25052), fatty acids including PUFAs (class) (schneider2024fuelforthought pages 2-4, huang2024metabolicreprogrammingin pages 1-2). - Cell Types (CL): tumor-associated macrophages (including SPP1+ and SELENOP+ subsets), cancer-associated fibroblasts (FAP+ apCAFs, iCAFs), Tregs, CD8+ cytotoxic T cells, NK cells; SCLC neuroendocrine tumor cells (zuani2024singlecellandspatial pages 1-2, cui2025singlecellandspatial pages 1-3, xie2024molecularclassificationand pages 1-2, redin2024smallcelllung pages 1-3). - Anatomical Locations (UBERON): Lung (UBERON:0002048), bronchi/airways (UBERON:0002185), alveolus (UBERON:0005915); tertiary lymphoid structures in tumor boundaries (cui2025singlecellandspatial pages 1-3, zuani2024singlecellandspatial pages 1-2).

3) Biological Processes (GO) disrupted - MAPK cascade (GO:0000165); PI3K signaling (GO:0014065); regulation of Hippo signaling (GO:0035329); Notch signaling (GO:0007219); antigen processing and presentation of peptide antigen (GO:0019882); response to interferon-gamma (GO:0034341); glycolytic process (GO:0006096); oxidative phosphorylation (GO:0006119); glutamine metabolic process (GO:0006541); epithelial to mesenchymal transition (GO:0001837) (liang2024hippopathwayin pages 1-2, zuani2024singlecellandspatial pages 1-2, schneider2024fuelforthought pages 2-4, huang2024metabolicreprogrammingin pages 1-2, xie2024molecularclassificationand pages 1-2).

4) Cellular Components - Plasma membrane (receptor tyrosine kinases; PD-1/PD-L1); nucleus (YAP/TAZ–TEAD transcriptional complexes); mitochondrion (OXPHOS); extracellular space/extracellular vesicles; tumor stroma (CAF niches); tertiary lymphoid structures at tumor margins (liang2024hippopathwayin pages 1-2, zuani2024singlecellandspatial pages 1-2, cui2025singlecellandspatial pages 1-3).

5) Disease Progression - Sequence: AAH→AIS→MIA→IAC with rising mutations, chromosomal instability/whole-genome doubling, telomere shortening, increased stemness; immune evolution from innate to adaptive with immune checkpoint upregulation in later stages (May 2024; https://doi.org/10.21203/rs.3.rs-4396272/v1) (zhang2024theevolutionof pages 1-6). - Distinct phases: Treatment-naive TME shows macrophage reprogramming and checkpoint co-expression differences between LUAD/LUSC; post-neoadjuvant remodeling associates with SELENOP+ macrophages–apCAF–T cell spatial circuits in responders (May 2024; Apr 2025) (zuani2024singlecellandspatial pages 1-2, cui2025singlecellandspatial pages 1-3).

6) Phenotypic Manifestations (selected) - Systemic and respiratory: disease burden reflected by global mortality; SCLC aggressive clinical course with early dissemination; NSCLC and SCLC benefit heterogeneously from ICIs depending on TME signatures (Feb 2024 GLOBOCAN; May 2024 CASPIAN) (hendriks2024nonsmallcelllungcancer. pages 1-2, xie2024molecularclassificationand pages 1-2, sen2024emergingadvancesin pages 1-3). Note: Symptom-level phenotypes vary and are not the focus of the cited molecular sources; clinical phenotypes should be interpreted alongside standard oncology references.

Ontology-linked Annotations (knowledge-base ready) - Genes/Proteins (HGNC): EGFR; KRAS; ALK; ROS1; BRAF; MET; TP53; RB1; STK11; KEAP1; PDCD1; CD274; ASCL1; NEUROD1; POU2F3; YAP1; WWTR1 (TAZ) (ibodeng2023asnapshotof pages 4-5, redin2024smallcelllung pages 1-3, liang2024hippopathwayin pages 1-2, xie2024molecularclassificationand pages 1-2). - GO Biological Processes: GO:0000165; GO:0014065; GO:0035329; GO:0007219; GO:0019882; GO:0034341; GO:0006096; GO:0006119; GO:0006541; GO:0001837 (liang2024hippopathwayin pages 1-2, zuani2024singlecellandspatial pages 1-2, schneider2024fuelforthought pages 2-4, huang2024metabolicreprogrammingin pages 1-2). - Cell Types (CL): tumor-associated macrophage (CL:0000863) with SPP1+ and SELENOP+ phenotypes; cancer-associated fibroblast (ontology under fibroblast CL:0000057; stromal subtype FAP+ apCAF/iCAF); regulatory T cell (CL:0000815); CD8+ T cell (CL:0000625); NK cell (CL:0000623) (zuani2024singlecellandspatial pages 1-2, cui2025singlecellandspatial pages 1-3). - Anatomical (UBERON): UBERON:0002048 (lung); UBERON:0002185 (bronchus); UBERON:0005915 (alveolus) (zuani2024singlecellandspatial pages 1-2, cui2025singlecellandspatial pages 1-3). - Chemicals (CHEBI): CHEBI:17234 (glucose); CHEBI:24996 (lactate); CHEBI:25052 (glutamine); fatty acids (CHEBI class) (schneider2024fuelforthought pages 2-4, huang2024metabolicreprogrammingin pages 1-2). - Phenotypes (HP; examples relevant to lung cancer, to be mapped to clinical datasets): dyspnea (HP:0002094), cough (HP:0012735), hemoptysis (HP:0002105), weight loss (HP:0001824). Note: these HP terms are standard but not specifically sourced in the molecular citations above; use with clinical corroboration.

Evidence items with PMIDs/links/dates (selection) - Zuani et al., Nature Communications, May 2024, single-cell/spatial NSCLC TME atlas. URL: https://doi.org/10.1038/s41467-024-48700-8 (zuani2024singlecellandspatial pages 1-2). - Xie et al., Molecular Cancer, May 2024, CASPIAN ES-SCLC biomarkers. URL: https://doi.org/10.1186/s12943-024-02014-x (xie2024molecularclassificationand pages 1-2). - Redin/Quintanal-Villalonga/Rudin, Trends in Cancer, Oct 2024, SCLC profiling and plasticity. URL: https://doi.org/10.1016/j.trecan.2024.07.008 (redin2024smallcelllung pages 1-3, redin2024smallcelllung pages 9-11). - Liang et al., Cancer Gene Therapy, Mar 2024, Hippo pathway in NSCLC. URL: https://doi.org/10.1038/s41417-024-00761-z (liang2024hippopathwayin pages 1-2). - Schneider et al., Translational Lung Cancer Research, Dec 2024, metabolism targeting. URL: https://doi.org/10.21037/tlcr-24-662 (schneider2024fuelforthought pages 2-4). - Huang et al., Frontiers in Pharmacology, Dec 2024, metabolic reprogramming. URL: https://doi.org/10.3389/fphar.2024.1516650 (huang2024metabolicreprogrammingin pages 1-2). - Zhang et al., Research Square, May 2024, LUAD precursors evolution. URL: https://doi.org/10.21203/rs.3.rs-4396272/v1 (zhang2024theevolutionof pages 1-6). - Yadav et al., Cell Death Discovery, Sep 2024, miRNA and PD-1/PD-L1 in lung cancer. URL: https://doi.org/10.1038/s41420-024-02182-1 (yadav2024themirnaand pages 1-2). - GLOBOCAN 2022 (updated Feb 2024), global incidence/mortality. URL: https://gco.iarc.fr/today (hendriks2024nonsmallcelllungcancer. pages 1-2).

Notes and limitations - Where preprint (Research Square) evidence was cited for LUAD precursors, findings should be interpreted alongside peer-reviewed validation (zhang2024theevolutionof pages 1-6). - Exosomal PD-L1 is a rapidly evolving area; while conceptually important, direct 2023–2024 lung-cancer–specific exosomal PD-L1 mechanistic data were not cited from the available context and therefore are not asserted here without primary support.

Conclusion Lung carcinoma pathophysiology arises from convergent genetic drivers, adaptive pathway rewiring (MAPK, PI3K/AKT/mTOR, HIPPO/YAP–TAZ, NOTCH), immunoediting within a macrophage- and fibroblast-rich TME, metabolic plasticity governed by genotype and redox control, and epigenetic programs enabling lineage plasticity and immune evasion. Contemporary single-cell/spatial multi-omics and immunotherapy biomarker analyses refine actionable endotypes (e.g., SCLC-I; macrophage/CAF spatial niches) and guide targeted, metabolic, and immune combinations with biomarker stratification (zuani2024singlecellandspatial pages 1-2, xie2024molecularclassificationand pages 1-2, liang2024hippopathwayin pages 1-2, schneider2024fuelforthought pages 2-4).

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