Weekly Respiratory Research Analysis
This week’s respiratory literature highlights mechanistic and translational advances that converge on immune modulation and virus–host interactions. A mechanistic Immunity study defines a lung–heart axis whereby influenza-infected CCR2+ myeloid cells transmit infection to cardiomyocytes and drive IFNAR1-dependent cardiac injury, identifying a targetable node. Integrated multi-omics work in Med links COPD-driven epithelial remodeling to enhanced anti–PD-1 responses in NSCLC via a spatial CXCL14–C
Summary
This week’s respiratory literature highlights mechanistic and translational advances that converge on immune modulation and virus–host interactions. A mechanistic Immunity study defines a lung–heart axis whereby influenza-infected CCR2+ myeloid cells transmit infection to cardiomyocytes and drive IFNAR1-dependent cardiac injury, identifying a targetable node. Integrated multi-omics work in Med links COPD-driven epithelial remodeling to enhanced anti–PD-1 responses in NSCLC via a spatial CXCL14–CXCR4 tumor–macrophage circuit. Complementing these, a Nature Communications program identifies DNA-PKcs (PRKDC) as a druggable hub whose inhibition activates cGAS/STING via MYC degradation to sensitize small-cell lung cancer to immunotherapy.
Selected Articles
1. Influenza hijacks myeloid cells to inflict type-I interferon-fueled damage in the heart.
This mechanistic study demonstrates that after pulmonary influenza infection, CCR2-high circulating pro-DC3 myeloid cells become infected, home to the CCL2-rich heart, and release virus that infects cardiomyocytes, triggering type I interferon (IFN-I) production and IFNAR1-dependent cardiac tissue injury. Cardiomyocyte-specific dampening of IFNAR1 protected heart function without compromising pulmonary antiviral immunity.
Impact: Identifies a previously unrecognized lung–heart axis and a tractable signaling node (cardiomyocyte IFNAR1) linking respiratory viral infection to cardiac injury, opening paths for organ-targeted interventions to reduce cardiovascular complications of influenza.
Clinical Implications: Suggests development of transient, cardiomyocyte-targeted IFN-I pathway modulators as a strategy to prevent influenza-associated cardiac complications and supports evaluation of biomarkers (e.g., CCR2+ pro-DC3 signatures) for early cardiac risk stratification.
Key Findings
- CCR2-high circulating pro-DC3 myeloid cells become infected after pulmonary influenza and are chemoattracted to the heart.
- Infected pro-DC3 release virus in the myocardium leading to cardiomyocyte infection, IFN-I production, and IFNAR1-dependent tissue injury and dysfunction.
- Cardiomyocyte-specific genetic/therapeutic dampening of IFNAR1 protects cardiac tissue without impairing lung antiviral immunity.
2. COPD reshapes the tumor microenvironment of NSCLC and enhances anti-PD-1 therapy response.
Integrated multi-omics across three clinical cohorts showed COPD drives epithelial remodeling that expands a basal-like tumor subset and activates a CXCL14–CXCR4 axis recruiting CXCL9+ macrophages, generating a spatial tumor–macrophage niche permissive for cytotoxic T-cell infiltration. This circuit was functionally validated and enriched in patients with major pathologic response to neoadjuvant anti–PD-1 therapy.
Impact: Provides a mechanistic explanation for improved PD-1 blockade responses in NSCLC patients with COPD and identifies a spatial epithelial–myeloid axis (CXCL14–CXCR4) with biomarker and interventional potential to optimize immunotherapy.
Clinical Implications: The CXCL14–CXCR4 tumor–macrophage signature could be prospectively validated as a predictive biomarker for PD-1 benefit in COPD–NSCLC and supports trials testing CXCR4-targeted strategies or microenvironment modulation to augment immunotherapy.
Key Findings
- COPD expanded a basal-like tumor cell population with progenitor-like features in NSCLC.
- A dominant CXCL14–CXCR4 axis recruited CXCL9-producing macrophages, enabling cytotoxic T-cell infiltration.
- The spatial tumor–macrophage circuit was functionally validated and enriched in patients achieving major pathologic response to neoadjuvant anti–PD-1 therapy.
3. Targeting NHEJ activates STING signaling through MYC degradation to boost antitumor immunity in SCLC.
Pan-cancer analysis (>179,000 tumors) and preclinical models identify PRKDC (DNA-PKcs) as highly expressed in SCLC and predictive of poor immunotherapy response. DNA-PKcs inhibition leads to cytosolic dsDNA accumulation, cGAS/STING activation, and GSK3β-dependent proteasomal MYC degradation, collectively increasing tumor immunogenicity and sensitizing SCLC models to checkpoint blockade.
Impact: Positions DNA-PKcs as a biomarker and druggable hub connecting DNA repair, oncogene regulation, and innate sensing—offering a rational strategy to overcome immunotherapy resistance in an otherwise refractory lung cancer subtype.
Clinical Implications: Supports clinical evaluation of DNA-PKcs inhibitors in combination with PD-1/PD-L1 blockade for SCLC, with PRKDC expression and MYC/STING signatures as candidate stratification biomarkers.
Key Findings
- PRKDC (DNA-PKcs) expression is highest in SCLC across 24 tumor types and predicts poor immunotherapy response.
- DNA-PKcs depletion/inhibition causes cytosolic dsDNA accumulation, activating the cGAS/STING pathway and increasing tumor immunogenicity.
- DNA-PKcs loss triggers GSK3β-dependent proteasomal degradation of MYC, linking NHEJ inhibition to oncogene downregulation and immunotherapy sensitization.