Comprehensive genomic profiling (CGP) is increasingly important for identifying actionable driver mutations and selecting targeted therapies in advanced lung adenocarcinoma, particularly when tissue re-biopsy is precluded by severe complications. A 74-year-old woman with no history of smoking presented with hemoptysis and abnormal findings on chest imaging. She was diagnosed with lung adenocarcinoma, cT2bN2M1c, Stage IVB, with bone and brain metastases. Initial molecular testing using AmoyDx® (AmoyDx Essential NGS Panel, Amoy Diagnostics, Xiamen, China) did not reveal any actionable driver mutations. Despite multiple lines of systemic therapy and whole-brain irradiation, the disease progressed with multiple liver metastases and cancer-associated disseminated intravascular coagulation (DIC). Given the patient's never-smoking status and the lack of residual tissue for repeat testing, comprehensive liquid biopsy-based genomic profiling was performed using FoundationOne® Liquid CDx (Foundation Medicine, Boston, MA, US). This analysis identified a human epidermal growth factor receptor 2 (HER2) exon 20 insertion mutation (p.G776delinsAVGC). Treatment with trastuzumab deruxtecan (T-DXd) resulted in marked tumor shrinkage and prompt resolution of DIC. During the sixth cycle of T-DXd, the patient developed Grade 3 drug-induced interstitial lung disease (ILD)/pneumonitis, necessitating permanent discontinuation of T-DXd and high-dose corticosteroid therapy. Subsequently, the patient developed carcinomatous meningitis and was transitioned to palliative care. This case demonstrates that liquid biopsy-based CGP can identify actionable alterations and enable life-saving targeted therapy in patients with advanced lung adenocarcinoma complicated by severe DIC; however, severe drug-induced toxicities, such as ILD, remain a critical bottleneck that requires careful monitoring to balance treatment efficacy and safety.

Catalytic nanomedicines face a persistent trade-off between structurally defined active sites and rapid synthesis. A microwave-assisted salt-flux conversion is developed that transforms a bimetallic metal-organic framework precursor within 3 min into nitrogen-doped carbon-supported ZnMn dual-atom nanozymes (ZnMn DAzymes). Aberration-corrected HAADF-STEM and dual-edge X-ray absorption fine structure analyses support adjacent Zn-Mn sites with an N-dominated ZnMn-N6-like coordination motif. Steady-state kinetics and density functional theory calculations suggest cooperative catalysis: Zn modulates H2O2 adsorption and O-O bond activation, whereas Mn provides stronger H2O2 chemisorption and redox flexibility, jointly enhancing catalase-, peroxidase-, and oxidase-like activities. The resulting cascade decomposes H2O2, relieves hypoxia, generates reactive oxygen species, and depletes glutathione, inducing mitochondrial dysfunction, immunogenic cell death, cGAS-STING-associated signaling, dendritic-cell maturation, and effector T-cell infiltration. Glutathione-responsive Mn2+ release additionally enables activatable T1-weighted magnetic resonance contrast. Combined with αPD-L1, ZnMn DAzymes suppress primary and distal tumors by approximately 90%, reduce lung metastases by 92%, and prolong survival in 4T1 models. This work provides a rapid route to ZnMn dual-atom nanozymes for catalytic immunotherapy.

Pulmonary metastasis remains a lethal challenge, necessitating potent mRNA vaccines to establish proactive immune surveillance. Although lipid nanoparticles (LNPs) are the gold standard for delivery mRNA, the "PEG dilemma"-comprising immunogenicity and poor cellular engagement-critically limits their efficacy. Here, we developed a biocompatibility, PEG-free mRNA platform (SG-LNP) co-modified with sialic acid-dimyristoyl-glycerol (SA-DMG) and monosialotetrahexosylganglioside (GM1), enabling a customizable tissue-targeting delivery pathway. This platform leverages the SA-Siglec axis to target antigen-presenting cells (APCs), markedly enhancing APCs uptake and facilitating endosomal escape. Upon pulmonary inhalation, the vaccine directly targets pulmonary APCs, shortening immunological pathways and enabling in situ priming of multiple immune effector cells (dendritic cells, macrophages, natural killer cells, and T cells). Following intravenous administration, it selectively targets splenic APCs to orchestrate a systemic immune surveillance network. Furthermore, leveraging this vaccine platform with tunable delivery routes, we investigated the contributions of local and systemic immune toward the prevention of tumor lung metastasis. We found that inhaled SG-LNP elicit robust local immune activation, leading to markedly reduced melanoma infiltration in the lungs relative to conventional PEG-modified LNPs. Notably, systemic administration of SG-LNP drives more extensive expansion of circulating antigen-specific T cells and natural killer cells (NKs). This systemic mobilization effectively intercepts circulating tumor cells before pulmonary colonization, achieving complete prevention of pulmonary metastasis with 100% protective efficacy. Our findings demonstrate that systemic coordination outperforms localized activation in prophylactic of organ-specific metastasis, providing a strategic blueprint for the design and administration of next-generation PEG-free mRNA vaccines.

Despite substantial treatment improvements, the 5-year survival rate for metastatic osteosarcoma (OS) is still as low as 20%. Immunocompetent genetic mouse models of OS have been introduced, enabling in vivo OS studies. Here, we present the ROCCIA mouse, a quintuple-mutant extension of these models that develops multifluorescent OS tumors, allowing distinct fluorescently labeled OS cell populations to be identified and traced both within tumors and in the circulation. In addition, this model enables postnatal inactivation of the p53 and Rb1 genes, thus resembling development and progression of OS in humans. Using this model, we show that osterix (Osx)-expressing fluorescent tumor cells appear in circulation upon OS development and predominate in lung metastases, thus representing a potential target for future therapies. We also show that the immunological landscape of this model's tumor microenvironment mimics the previously described human OS microenvironment. Therefore, this immunocompetent, quintuple mutant, multifluorescent mouse model represents a powerful resource to analyze OS tumor development and metastasis in real time and to test translational therapies.

Amivantamab is an epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) antibody. Lazertinib is an EGFR tyrosine kinase inhibitor with central nervous system penetration. Used in combination, this targeted therapy is effective in treating non-small cell lung cancer (NSCLC). However, it has been associated with severe dermatologic adverse reactions. A 61-year-old woman with a history of EGFR-mutated NSCLC with brain metastases on amivantamab-lazertinib therapy presented for follow-up with drainage from her scalp incision after undergoing a right parietal craniotomy and mass excision five months prior. The patient denied constitutional and neurologic symptoms, but reported yellow staining on her pillow. Examination initially demonstrated yellow fibrinous exudate and hair matting along the surgical incision. Computed tomography (CT) of the head revealed overlying scalp swelling and minimal extra-axial dural thickening over the prior right parietal craniotomy site with stable intracranial metastatic lesions. Due to concern for dehiscence, her biologic therapy was paused, and she was taken to the operating suite where no evidence of infection, delayed healing, or wound dehiscence was noted. A 10 × 5 cm area of patchy granulation tissue and ulceration was observed along the right parietal scalp. Biopsy revealed granulation tissue and multinucleated giant cells and was negative for tumor. Given the risk of malignant progression with all targeted therapy paused, the patient was restarted on amivantamab monotherapy. Following disease progression two months later, she was transitioned to carboplatin and etoposide. EGFR is widely expressed in skin keratinocytes and intimately involved in epithelial differentiation. Therapies targeting EGFR, such as amivantamab plus lazertinib, are associated with adverse dermatologic reactions, ranging from dry skin to severe scalp ulceration, which can interrupt treatment, contribute to poorer clinical outcomes, and reduce quality of life. Standard of care includes limiting sun exposure and avoiding alcohol-based topical agents. The use of daily prophylactic antibiotics, such as oral doxycycline, topical clindamycin, chlorhexidine wash, and ceramide moisturizer, may significantly reduce the risk of adverse skin reactions. Implementation of this multicomponent regimen reduced the rate of severe scalp reactions from 26% to 10% relative to the standard of care, with sustained benefit observed for at least six months.

Immunotherapy in combination with chemotherapy has been recommended as the first-line treatment of driver gene-negative advanced non-small cell lung cancer (NSCLC), but the efficacy is reduced in NSCLC patients with bone metastases due to the immunosuppressive microenvironment. Both nuclear factor kappa-B ligand (RANKL) inhibitors and stereotactic body radiation therapy (SBRT) have been shown to modulate the tumour immune microenvironment. Therefore, narlumosbart, a monoclonal antibody targeting RANKL, in combination with SBRT, may exert synergistic effects and improve efficacy of first-line chemoimmunotherapy in this population.

IntroductionLymph node (LN) metastasis of lung adenocarcinoma, particularly occult lymph node metastasis (OLNM), remains difficult to predict using conventional imaging and basic positional parameters, adversely affecting prognosis. This study aimed to: (1) evaluate a new CT index (a/A + b/B) for predicting OLNM in cN0 patients, and (2) create and validate a nomogram for predicting LN metastasis probability in CT-suspected cases.MethodsThis single-center retrospective study involved 387 lung adenocarcinoma patients (225 non-LN, 84 OLNM, and 78 with CT-suspected/pathologically confirmed LN metastasis) who had surgery from 2016 to 2024. A spatial index (a/A + b/B) was developed to combine two perpendicular anatomical axes, vertical proximity to the interlobar fissure and horizontal proximity to the mediastinum/hilum, into one standardized metric.ResultsThe combined ratio a/A + b/B was significantly lower in the OLNM and metastatic groups. A lower a/A + b/B was significantly associated with OLNM (OR = 0.175, 95% CI: 0.048-0.638, P = 0.007), suggesting a 0.1-unit decrease in the a/A + b/B ratio increased OLNM risk by 19%. A nomogram utilizing a/A + b/B differentiates CT-suspected LN metastasis from node-negative cases, showing AUCs of 0.83 (95% CI: 0.76-0.90) in training, 0.85(95% CI: 0.76-0.94) in internal validation, and 0.70(95% CI: 0.50-0.91) in external validation.ConclusionA ratio of a/A + b/B < 0.6 indicates a high OLNM risk in cN0 patients. This index can predict OLNM when LNs are small on CT, and a nomogram can differentiate CT-suspected LN metastasis from node-negative cases, meriting further study.