Faculty Bibliography

BACKGROUND AND OBJECTIVE/UNASSIGNED:Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung carcinoma cases and is often diagnosed at an advanced stage, leading to poor prognosis. Local tumor ablation is an emerging treatment option; however, thermal ablation techniques, such as radiofrequency ablation (RFA) or microwave ablation (MWA), can have many adverse events, such as a negative impact on the extracellular matrix (ECM) architecture, promoting tumor progression. Pulsed electric field (PEF) therapy is a non-thermal modality that induces electrostimulatory pulses, which can preserve the ECM architecture while stimulating anti-tumor immune responses. This narrative review evaluates the safety, efficacy, and immunomodulatory potential of PEF therapy in NSCLC. METHODS/UNASSIGNED:A comprehensive literature search was conducted in Google Scholar, MEDLINE, Embase, Scopus, PubMed, Web of Science, UpToDate, and the Cochrane Library through October 1, 2025. Eligible studies included adult patients (≥18 years) with histologically confirmed NSCLC treated with PEF. Two independent reviewers screened studies and extracted data on patient demographics, tumor characteristics, treatment modalities, adverse events, and outcomes. KEY CONTENT AND FINDINGS/UNASSIGNED:33%) compared with standard systemic therapy. CONCLUSIONS/UNASSIGNED:PEF may play a role in stimulating an anti-tumor response and represents a promising, safe, non-thermal ablation modality for NSCLC treatment. It preserves ECM integrity while inducing local and systemic immunomodulatory effects. Early clinical evidence suggests potential efficacy. Nevertheless, randomized controlled trials are required to confirm clinical benefit and identify the patient populations most likely to benefit from PEF therapy.

Recent advances have furthered our understanding of the role of the tumor draining lymph node (TDLN) in the immune response to thoracic malignancies. This review synthesizes the rapidly expanding evidence that tumor draining lymph nodes (TDLNs) are not passive conduits of metastasis but dynamic immunologic organs that shape anti-tumor immunity in non-small cell lung cancer (NSCLC). Across cytokine, cellular, genomic, transcriptomic, and metabolic domains, the TDLN microenvironment becomes progressively remodeled towards immune suppression. These changes influence tumor growth and early metastasis, and may dictate responsiveness to various treatment modalities. The TDLN is also a practical and clinically relevant site for biomarker discovery and therapeutic innovation as a target of drug delivery and immunomodulation.

The abscopal effect, first described in 1953, refers to the regression of distant, non-irradiated tumors following localized therapy. Historically considered rare, interest in this phenomenon has increased with the introduction of immunotherapy and local treatments for non-small cell lung cancer (NSCLC). This review summarizes the current evidence on the pathophysiology, clinical observations, and assessment of the abscopal effect in NSCLC following radiotherapy, lung ablation, and combined multimodality therapies. Preclinical and early clinical studies suggest that radiotherapy and ablative techniques such as cryoablation, microwave ablation, and pulsed electric field therapy may induce immunogenic cell death, leading to the release of tumor antigens and danger-associated molecular patterns that can activate systemic antitumor immune responses. When combined with immune checkpoint inhibitors, these local therapies may enhance immune activation, potentially improving both local and distant tumor control. However, recognition of abscopal effects remains inconsistent, largely due to limitations of conventional response assessment criteria. While iRECIST partly captures atypical response patterns, unequivocal out-of-field tumor regression is not systematically recorded in most clinical trials. The available evidence, primarily from preclinical models and early-phase studies, suggests that the true incidence of abscopal effects in NSCLC may be underrecognized. Accordingly, we propose a working definition of the abscopal effect in NSCLC: the regression (complete or partial response by iRECIST) of one or more non-irradiated lesions distant from the primary treatment site, occurring after localized therapy with or without systemic treatment, and confirmed by follow-up imaging within 4-8 weeks. Establishing standardized terminology and assessment criteria will be essential for accurately identifying and integrating potential abscopal responses in future NSCLC research and clinical practice.

Lung cancer is the leading cause of cancer deaths, and despite therapeutic advances, recurrence and resistance persist. Local tumor ablation can function as an in situ vaccine, but thermal techniques may disrupt antigen and extracellular matrix integrity, potentially limiting immunogenicity, whereas cryoablation has been shown to preserve tumor antigens and matrix architecture while inducing immunogenic cell death. Bronchoscopic cryoimmunotherapy (BCI) aims to prime antitumor immunity rather than achieve complete tumor eradication. We review preclinical and clinical studies evaluating cryoablation and BCI in non-small cell lung cancer (NSCLC), focusing on immune mechanisms, delivery approaches, and combination with systemic therapies, particularly immune checkpoint inhibitors (ICIs). Preclinical models demonstrate that cryoablation releases danger signals and intact tumor antigens, drives dendritic cell maturation, expands effector CD8+ T cells, and activates STING-dependent type I interferon pathways. Early-phase human studies of BCI monotherapy show systemic immune stimulation, including reductions in the derived neutrophil-to-lymphocyte ratio and expansion of CD8+ effector memory populations. Combination cryoablation-ICI regimens have revealed improved response rates in some cohorts, although clinical outcomes have been limited by small, heterogeneous, and non-randomized studies. BCI is a mechanistically compelling, minimally invasive therapy, but its clinical benefit remains unproven and warrants rigorous randomized evaluation.

INTRODUCTION/UNASSIGNED:Outcomes for NSCLC remain suboptimal. Recent data suggest that cryoablation can generate antitumor immune effects. In this first-in-human phase I clinical trial, we investigated the safety and feasibility of bronchoscopic cryoimmunotherapy (BCI) delivered during standard-of-care bronchoscopy and explored associated systemic immune responses. METHODS/UNASSIGNED:Subjects with known or suspected advanced-stage NSCLC were recruited. BCI was delivered in dose-escalated freeze-thaw cycles to determine maximum dose tolerance. Feasibility assessment was determined with a pre-set goal of achieving successful BCI in more than or equal to 80% of subjects. Safety was assessed by review of BCI-related complications, including grades 2 to 3 bleeding, pneumothorax requiring intervention, and National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 to 5 adverse events. Pre- and post-BCI blood samples were collected to explore changes in the systemic immune profile. RESULTS/UNASSIGNED:Subjects with predominantly clinical TNM stage 3 or 4 adenocarcinoma or squamous cell carcinoma were enrolled. We reached the maximum dose of 30 seconds with 100% feasibility and no BCI-related adverse events. In peripheral blood analysis, we observed a significant decrease in derived neutrophil-to-lymphocyte ratio in the high-dose BCI group in comparison to the low-dose BCI cohort. We also observed increases in inflammatory cytokines-GM-CSF, IFN-γ, IL-1β, IL-17A, and IL-2-and effector memory T cells post-BCI. CONCLUSION/UNASSIGNED:BCI is safe and feasible. In addition, we provide preliminary evidence that at higher dose levels there is a systemic immune response consistent with a cytotoxic profile. Further immune analyses will determine the potential of BCI as an adjunctive therapy in combination with immune checkpoint inhibition in NSCLC treatment.

BACKGROUND:Advanced-stage non-small cell lung cancer treatment has evolved with the introduction of molecularly targeted therapy, immunotherapy and combination frontline therapies. Despite these advancements, most patients experience treatment failure, resulting in poor prognosis characterized by low median progression-free survival (PFS) and overall survival (OS). Second-line chemotherapy has demonstrated minimally improved survival compared to best supportive care. Exploring new mechanisms to enhance treatment response in this patient population is critical. OBJECTIVE:This retrospective study aims to assess if there is survival benefit in a cohort of patients with stage IV lung cancer who have failed previous systemic therapy treated with pulsed electrical fields (PEF) therapy compared to a propensity-matched cohort. METHODS:A retrospective review of patients treated with PEF at three academic institutions from January 1, 2023, to July 1, 2024, yielded 41 patients with progressive stage IV non-small cell lung cancer. Tumor response was evaluated by RECIST 1.1 criteria. A propensity matched cohort of 50 patients with advanced NSCLC undergoing systemic therapy was identified. Statistical analyses, including Kaplan-Meier survival estimates and Hazard ratios, were conducted. RESULTS:The PEF-treated cohort exhibited a 1-year PFS of 63.2 % and OS of 74.3 %. In contrast, the matched cohort demonstrated a 1-year PFS of 11.8 % and OS of 33 %. The hazard ratio for PFS in the PEF group was 3.66 (p < 0.0001) and for OS was 3.5 (p = 0.0007), indicating a significant survival advantage for patients receiving PEF. CONCLUSION/CONCLUSIONS:This study suggests that PEF therapy may be associated with significantly improved PFS and OS in patients with progressive stage IV non-small cell lung cancer compared to the matched cohort. Prospective controlled studies are required to confirm these preliminary findings, to better understand the mechanism of action of PEF, and to identify which patient populations would best benefit from this therapy.

How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

BACKGROUND:It remains challenging to safely and reliably biopsy peripheral pulmonary lesions (PPLs). Robotic-assisted bronchoscopy (RAB) is gaining adoption for navigation to PPLs. However, evidence from large studies remains limited. RESEARCH QUESTION/OBJECTIVE:What is the clinical safety, navigational success, and diagnostic yield of RAB for biopsy of PPLs in a broad range of patients in a real-world setting? STUDY DESIGN AND METHODS/METHODS:This multicenter, prospective, single-arm study enrolled patients >21 years old with 8-50 mm lung lesions requiring bronchoscopic diagnosis. The primary endpoint was the incidence of the following device- or procedure-related events: (1) pneumothorax requiring intervention; (2) bleeding requiring intervention; or (3) respiratory failure. Secondary endpoints included individual components of the primary endpoint, procedure time, pneumothoraces, radial probe endobronchial ultrasound (R-EBUS) confirmation, conversion to an alternative biopsy procedure, complications, and diagnostic yield (DY). RESULTS:Among 715 patients at 21 sites, 679 met study criteria and underwent RAB (mean age 68.7, 55.4% female, 86.5% White, 77.5% current/past tobacco users). Mean (range) lesion size was 20.9 (7.0-63.0) mm; median (IQR) distance from pleural surface was 5 (0-16) mm. Most lesions were solid (n=587; 86.6%) and within the outer two-thirds of the lung (n=593; 87.5%). The primary endpoint was observed in 26 (3.8%) patients (19 pneumothorax, 7 bleeding, 0 respiratory failure). Users reported that RAB reached the lesion in 670/679 (98.7%) cases, and lesion location was confirmed with R-EBUS in 607/662 (91.7%) cases; sampling through the bronchoscope was performed in 675/679 (99.4%) cases. Prevalence of malignancy was 64.1% through 12 months. Adjudicated DY was 61.6% when calculated with the American Thoracic Society (ATS)/American College of Chest Physicians (ACCP) definition for strict reporting criteria. Sensitivity for malignancy was 78.8%. INTERPRETATION/CONCLUSIONS:This largest multicenter prospective study of RAB to date demonstrated that RAB-guided sampling of PPLs is safe and compares favorably to results from sizable non-robotic bronchoscopy studies. CLINICAL TRIAL REGISTRATION NUMBER/BACKGROUND:NCT04182815.

The role of dietary fiber in colon cancer prevention remains controversial. We investigated its impact on anti-tumor immunity and the gut microbiota in APCmin/+ mice infected with Enterotoxigenic Bacteroides fragilis. Mice were fed high-fiber, low-fiber, or chow diets, and tumor burden, survival, cytokines, microbiota, and metabolites were analyzed. Contrary to the belief that high fiber inhibits tumor progression, it had no significant impact compared to chow diet. However, the low-fiber diet significantly reduced tumor burden and improved survival. Mechanistically, high fiber increased pro-inflammatory cytokines and CD4+Foxp3+RORγt+IL-17A+ regulatory T cells, while low fiber enhanced anti-inflammatory cytokines and cytotoxic T-cells. High fiber enriched microbial taxa associated with IL-17A+RORγt+ Tregs and altered metabolites, including reduced tryptophan and increased short-chain fatty acids and bile acids. Low fiber produced opposite effects. These findings suggest that dietary fiber's effects on colon cancer depends on microbial infection and immune status, emphasizing the need for personalized dietary interventions in colon cancer management.

Studying lung adenocarcinoma (LUAD) early carcinogenesis is challenging, primarily due to the lack of LUAD precursors specimens. We amassed multi-omics data from 213 LUAD and LUAD precursors to identify molecular features underlying LUAD precancer evolution. We observed progressively increasing mutations, chromosomal aberrations, whole genome doubling and genomic instability from precancer to invasive LUAD, indicating aggravating chromosomal instability (CIN). Telomere shortening, a crucial genomic alteration linked to CIN, emerged at precancer stage. Moreover, later-stage lesions demonstrated increasing cancer stemness and decreasing alveolar identity, suggesting epithelial de-differentiation during early LUAD carcinogenesis. The innate immune cells progressively diminished from precancer to invasive LUAD, concomitant with a gradual recruitment of adaptive immune cells (except CD8₊ and gamma-delta T cells that decreased in later stages) and upregulation of numerous immune checkpoints, suggesting LUAD precancer evolution is associated with a shift from innate to adaptive immune response and immune evasion mediated by various mechanisms.