Abstract High-grade serous ovarian cancer (HGSOC) is the most common (≈80%) and lethal subtype of ovarian cancer in the United States. HGSOC is characterized by universal TP53 mutations, genomic instability, and defects in DNA damage repair (DDR) pathways, which often lead to chromosomal instability (CIN). The cytoskeletal motor protein KIF18A is essential for chromosomal congression and segregation during metaphase in CIN+ cancer cells but not necessary in normal cells. We recently demonstrated that a novel KIF18A inhibitor, ATX020 (tool compound), specifically inhibits cell growth in HGSOC cells with higher ploidy and aneuploidy scores (AS), which are markers of CIN (Nair et al, Cancers, 2025). It does this by blocking the plus-end movement of KIF18A from spindle poles and disrupting chromosomal congression and segregation. In that study, we also observed increased WEE1 activity in resistant cells treated with ATX020, as indicated by higher levels of its phosphorylated substrate CDK1 (pCDK1-Y15), a key component of the G2/M cell cycle checkpoint. WEE1 inhibitors can make cells more sensitive to DNA-damaging agents by overriding the G2/M checkpoint and forcing cells with unrepaired DNA damage into premature mitosis, leading to increased DNA damage and CIN. Furthermore, recent RNAseq analysis shows enrichment of pathways involved in regulating the G2/M checkpoint and DNA damage repair in cells treated with ATX020 cells. We hypothesized that targeting WEE1 could enhance sensitivity of both resistant and sensitive cells to ATX020. We used ATX020 resistant (A2780, PEO4, and OVCAR5) and sensitive (OVCAR3, OVCAR8, and PEO1) cell lines to examine the effects of an WEE1 inhibitor, AZD1775 (Adavosertib), on inducing CIN and thus sensitivity to ATX020. Using multi-well growth inhibition assays, immunofluorescent microscopy, live cell imaging, westerns and flow cytometry, we show that WEE1 inhibition made both resistant and sensitive HGSOC cells more responsive to ATX020, while also increasing DNA damage, prolonging/disrupting mitotic process and causing proliferative arrest. Transcriptomic analysis (bulk RNAseq) and differential gene expression (DEG) analysis show consistent upregulation of target genes and associated pro-inflammatory pathways, TNF signaling, and epithelial-mesenchymal transition in both sensitive and resistant cells when treated with ATX020. This uncovers potential targets that could improve the efficacy of ATX020 in preclinical models. Furthermore, murine models of both resistant and sensitive HGSOC cells treated with ATX020 exhibit tumor growth inhibition that is consistent with the in vitro results. These findings suggest new research approaches that could potentially enhance the impact of KIF18A inhibition in a clinical setting. Citation Format: Jayakumar R. Nair, Tzu-Ting Huang, Maureen Lynes, Serena Silver, Laura Ghisolfi, Stanley Lipkowitz, Jung-Min Lee. Inhibiting WEE1 kinase enhances sensitivity of high grade serous ovarian cancer cells to the novel KIF18A inhibitor ATX020 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB056.

Abstract Leptomeningeal metastases (LM) are a severe and fatal complication of advanced HER2-positive breast cancer, with limited effective treatment options. Robust preclinical models are needed to better understand LM biology and to evaluate novel therapeutic strategies. We developed an athymic nude mouse model of LM using human HER2-positive JIMT1-BR3 breast cancer cells selected for leptomeningeal tropism (JIMT1-BR3-LM4). Leptomeningeal tumor progression was evaluated using bioluminescence imaging, magnetic resonance imaging, histopathology, and immunofluorescent analyses. Therapeutic efficacy of two doses of trastuzumab deruxtecan (T-DXd) was compared with trastuzumab, nab-paclitaxel, and trastuzumab plus nab-paclitaxel. Pharmacodynamic effects, drug distribution, lesion burden, and survival were assessed. Bulk RNA sequencing was performed to identify molecular alterations associated with leptomeningeal tropism. T-DXd demonstrated dose-dependent antitumor activity, with the higher dose producing marked reductions in leptomeningeal tumor burden in the brain and spine, as well as decreased lesion number, lesion size, and associated edema. T-DXd significantly reduced tumor cell proliferation and increased apoptosis within leptomeningeal lesions. Drug distribution to leptomeningeal lesions was comparable to, or slightly lower than, trastuzumab. T-DXd reduced both leptomeningeal and limited parenchymal brain metastases and produced similar pharmacodynamic effects in both compartments. Treatment with T-DXd significantly prolonged survival, with a subset of animals exhibiting durable long-term survival. Bulk RNA sequencing identified top pathway alterations, including cytokine–cytokine receptor interactions, calcium signaling, cell adhesion molecules, and TNF signaling. LINC01638, POSTN, and VCAM1 were identified as top differentially expressed genes. Validation of these genes is underway. These findings support clinical evaluation of T-DXd for HER2-positive LM and establish this model as a valuable platform for therapeutic discovery.

Abstract Background: Sacituzumab govitecan (IMMU-132) is an antibody drug conjugate targeting trophoblastic cell surface antigen 2 (Trop2) that’s approved for treatment of patients with metastatic TNBC who have received two or more prior systemic therapies. The cytotoxic payload of IMMU-132 is a topoisomerase I inhibitor (SN-38) that kills cancer cells by causing DNA damage. Efforts to enhance the efficacy of IMMU-132 treatment include combination therapy with other agents. Apo2L/TRAIL interacts with death receptors on the cell surface to induce apoptosis in cancer cells, sparing normal cells. We previously have shown that TNBC is most sensitive to Apo2L/TRAIL. We investigated whether combination treatment with IMMU-132 and Apo2L/TRAIL synergistically inhibit TNBC cell growth. Methods: Human TNBC cell lines treated in vitro with IMMU-132 and Apo2L were assessed for cell viability via a propidium iodide-based cell death assay and ATP cell viability assay. The mode of cell death elicited by combination treatment was also investigated by using inhibitors of apoptosis, necroptosis and ferroptosis. Effects of treatment on cell cycle arrest were explored using flow cytometry. In vivo, NCr athymic nude (nu/nu) female mice with HCC1806 TNBC xenografts were treated with IMMU-132 and Apo2L after which tumor growth and survival were monitored. Results: Combination treatment with IMMU-132 and Apo2L synergistically induced cell death in triple negative breast cancer cell lines with high Trop2 expression (e.g. HCC1806, MDA-MB-468) but did not in the Trop2 low expressing MDA-MB-231 cell line. In some Trop2 low TNBC cell lines (e.g. BT-549, SUM-159), combination treatment also showed synergistic induction of cell death, suggesting extracellular deconjugation of the SN-38 cytotoxic payload and diffusion into cells. The synergy seen in Trop2 low TNBC cell lines was abrogated by limiting drug incubation periods - which minimizes the extracellular deconjugation. In contrast, the synergy seen in Trop2 high cells was maintained in these short incubation assays. Caspase activation assays and viability assays with caspase inhibitors showed that the primary mechanism of cell death for Apo2L and combination treatment with IMMU-132 is through apoptosis. Furthermore, flow cytometry-based cell cycle assays showed that IMMU-132 and combination treatment with Apo2L induce cell cycle arrest at the G2/M stage. Our xenograft model also showed significant antitumor effects with SG and TRAIL agonist combination treatment including decrease in tumor growth and improved survival in HCC1806 bearing mice. Conclusions: The data suggest a synergistic effect of combination treatment with Trop2 antibody drug conjugate IMMU-132 and TRAIL agonists in killing TNBC cells. Citation Format: Yonit Addissie, Yoshimi Endo Greer, Stan Lipkowitz. Synergistic lethality of combination treatment with Trop2-directed antibody-drug conjugate (IMMU-132) and Apo2L/TRAIL in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1771.

ONC201 is a first-in-class, FDA-approved small molecule activator of the mitochondrial ATP-dependent caseinolytic peptidase P (ClpP). This and other related small molecules referred to as ClpP agonists, exert antiproliferative effects in several cancer cell types. We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines. Senescence was determined by increased β-galactosidase (β-gal) activity, downregulation of phosphorylated Rb, c-Myc (Myc), and lamin B1, upregulation of senescent-associated secretory phenotype (SASP), and extended cell proliferation assays. These responses were not observed in ClpP knockout cell lines, demonstrating ClpP-dependence. Proteomics analyses identified multiple events related to the development of senescence including cell cycle arrest and mitochondrial dysfunction. Flow cytometry confirmed an S-phase arrest and DNA damage was detected by Comet assay, 53BP1, phospho-S*Q, and γH2A.X immunostaining. In parallel with this, activation of the ATM pathway and phosphorylation of Chk2 was observed. We determined that ClpP agonist-induced senescence was irreversible in both in vitro and in vivo studies. Following TR-57 treatment and drug washout, cells remained growth arrested which coincided with loss of mitochondrial membrane potential and ability to produce ATP by oxidative phosphorylation. β-gal staining after TR-57 treatment and drug washout demonstrated a sustained increase in β-gal activity, indicating cells are senescent after drug washout. This response was reproduced in vivo wherein senescent 4T1-Luc cells did not develop tumors following injection into mice. Finally, the combination of a ClpP agonist with a known senolytic (venetoclax), synergistically increased the amount of cell death observed. In summary, we show that ClpP agonists stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells.

Tumor NOS2 and COX2 expression induced by IFNg and TNFa

Leptomeningeal metastases are devastating complications of advanced HER2+ breast cancer, with limited therapeutic options. We developed a xenograft model of human HER2+ breast cancer cell line JIMT1-BR3-LM4 leptomeningeal colonization by four iterative cycles of intrathecal injection. The model reliably produced leptomeningeal lesions in brain and spinal cord and tumor cells in the CSF, as confirmed by endpoints of BLI, MRI, pathologic analysis and immunofluorescent staining. Upon RNA-seq, the LM model exhibited significant transcriptional changes as compared to the starting brain-tropic line. In a preclinical experiment, two doses of trastuzumab deruxtecan (T-DXd) were compared to human IgG, trastuzumab (T), nab-paclitaxel (nab-P) and T + nab-P for leptomeningeal metastasis. T-DXd demonstrated efficacy in terms of BLI imaging of the brain (P < 0.0001) and spine (P = 0.008), leptomeningeal lesion number and size in the brain (P = 0.06); efficacy was dose-dependent. T-DXd 10 mg/kg reduced leptomeningeal tumor Ki67 positivity (P = 0.0008) and increased apoptosis (P < 0.0001). In the brain, a comparison of leptomeningeal and parenchymal lesion number showed a reduction by T-DXd of 53% and 72%, respectively, compared to human IgG, with comparable effects on tumor proliferation and apoptosis. T-DXd also extended median survival to 38 days compared with 20 -24 days in control IgG or T + nab-P, with some mice surviving beyond 60 days (P = 0.003). These findings support ongoing clinical translation of T-DXd for HER2+ leptomeningeal metastasis and highlight the value of this model for future therapeutic development.

SYNTHESIS-Breast is an exploratory trial that adapts early-phase design to identify off-label therapies in metastatic breast cancer via ENLIGHT, a retrospectively validated computational algorithm, and generate preliminary data for future trials. ENLIGHT selects treatments via gene-expression-based synthetic lethality/rescue. SYNTHESIS-Breast’s design includes algorithm-specific adaptations (ex. a reproducible molecular tumor board or layered Simon two-stages for fast interim checkpoints). SYNTHESIS-Breast will not only guide ENLIGHT applications, but also future prospective algorithm trials.

While Trastuzumab emtansine (T-DM1) and other HER2-targeting antibody-drug conjugates (ADCs) are used to treat cancer patients with HER2-amplified tumors, there is a need to improve the efficacy through the understanding of their mechanism of uptake into cells. Flotillin-2 (FLOT2) regulates the internalization of epidermal growth factor receptor (EGFR), leading us to investigate FLOT2 effects on HER2 internalization. Higher FLOT2 expression in nine HER2 amplified cell lines correlated with a higher T-DM1 IC50 in vitro, and breast cancer patients with high FLOT2 expression had worse survival when receiving either T-DXd (16.2 months (m) vs 18.3 m, p=0.04) or T-DM1 (38.0 m vs 41.3 m, p=0.1) in real-world Caris Life Sciences data. FLOT2 interacts with HER2 and positively regulates HER2 activation and downstream signaling, while FLOT2 knockdown reduces the viability of HER2 amplified cancer cells. FLOT2 knockdown results in increased HER2 internalization upon binding of T-DM1, mediated by ubiquitination by the Cbl ubiquitin ligases. We investigated the effects of various small molecules and discovered that zoledronic acid binds to FLOT2 and disrupts the HER2/FLOT2 interaction, which enhances T-DM1 internalization and cytotoxicity. In conclusion, FLOT2 regulates the internalization and cytotoxicity of T-DM1 mediated by Cbl-dependent ubiquitination of HER2. Zoledronic acid disrupts the HER2/FLOT2 interaction, therefore increasing the internalization and cytotoxicity of T-DM1, providing proof of principle that a small molecule inhibitor of the HER2/FLOT2 interaction can enhance the activity of the HER2-targeting ADC.

Abstract Tumor spatial organization critically shapes disease progression and therapeutic response, yet remains poorly defined. Intrahepatic cholangiocarcinoma (iCCA), a rare and aggressive liver malignancy with extensive stromal and immune remodeling, provides a compelling model to study tumor architecture. We generated a single-cell spatial atlas of 1 million cells from 131 iCCA patients using 53-plex spatial proteomics. To systemically characterize tumor spatial organization, we developed a graph-based deep learning framework to define cell type-centric interaction networks, identifying 41 distinct multicellular spatial patterns. Integration of these networks revealed higher-order tumor- and immune-enriched microenvironments associated with patient outcomes. Notably, neutrophil-associated tumor-enriched and tumor-desert microenvironments delineated patient groups with opposing clinical outcomes and distinct neutrophil states. These findings were validated by single-cell spatial transcriptomic profiling of 6 million cells from 162 iCCA patients. Together, this study defines the spatial architecture of iCCA and provides a comprehensive resource for exploring tumor spatial organization.

Supplementary Table I summarizes pathological features of tumor immune microenvironment where NOS2+ inflamed regions are significantly higher in tumors from Deceased patients.

Abstract Here we report the efficacy and translational findings of durvalumab, olaparib, and cediranib (D + O + C) and of durvalumab plus cediranib (D + C) from the recurrent ovarian cancer cohort within a single-center, multi-arm, non-randomized, multi-cohort phase I/II trial (NCT02484404). Sixty-eight patients were enrolled (39 in D + O + C, 29 in D + C). The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. ORR was 19.4% (95% CI, 9.5-43.5) for D + O + C and 29.6% (95% CI, 13.8-46.9) for D + C; D + C met the primary endpoint while D + O + C did not. Median PFS was 4.5 months in both arms, with four exceptional responders (PFS ≥ 12 months) per arm. Toxicity was manageable. Pre- and on-treatment biopsies and blood samples were collected for prespecified transcriptomic and immunophenotypic profiling; signature analyses and preclinical studies were conducted post hoc and were exploratory. Baseline tumors from exceptional responders and patients with clinical benefit (partial response or stable disease with PFS ≥ 4 months) demonstrated enrichment of immune activation and metabolic pathways, whereas tumors with no clinical benefit (NCB; progressive disease or stable disease with PFS < 4 months) exhibited upregulation of vascular adaptation and cytoskeletal remodeling pathways. These findings support the proof-of-concept clinical activity of D + O + C and D + C and identify molecular signatures with potential predictive value in subsets of recurrent ovarian cancer.

Spatial transcriptomics (ST) assays are transforming our understanding of tumor heterogeneity, but their high cost limits their application in large-scale biomarker discovery. Here, we present “Path2Space,” a deep-learning model that predicts spatial gene expression directly from histopathology slides. Trained on extensive breast cancer ST data, Path2Space robustly predicts the spatial expression of thousands of genes, outperforming 21 established methods. Charting the tumor microenvironment (TME) of 976 breast cancer TCGA (The Cancer Genome Atlas) tumors, it accurately infers cell-type abundances and identifies three spatially defined breast cancer subgroups with distinct survival outcomes. Notably, the derived low-cost spatial TME landscapes enable more accurate predictions of patient response to chemotherapy and trastuzumab compared with costly conventional bulk-sequencing-based biomarkers. Path2Space thus offers a scalable, fast, and cost-effective alternative to molecular assays. It opens avenues for large cohort treatment biomarker discovery and translationally relevant insights into tumor biology, with potential applicability across many cancer indications.

Abstract Background Sacituzumab govitecan (SG) is an antibody drug conjugate targeting trophoblast cell surface antigen 2 (Trop2) that is approved for treatment of patients with metastatic triple negative breast cancer (TNBC). Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) agonists are antitumor agents that interact with death receptors on the cell surface to induce apoptosis in cancer cells, often sparing normal cells. In this study, we investigated whether combination treatment with SG and TRAIL agonists inhibit TNBC cell growth. Methods In vitro, 10 human TNBC cell lines and 4 non-modified, low passage patient derived TNBC cells were treated with SG and the TRAIL agonist Apo2L. Cell death was assessed via a propidium iodide-based assay while cell proliferation was measured using an ATP cell viability assay. The mode of cell death elicited by combination treatment was investigated by using inhibitors of apoptosis, necroptosis and ferroptosis. The drug effect on cell cycle was analyzed with flow cytometry. In vivo, NCr athymic nude (nu/nu) female mice bearing HCC1806 TNBC xenografts were treated with SG and TRAIL agonists after which the effect of treatment on tumor growth and survival was evaluated. Results SG and TRAIL acted synergistically in all 10 TNBC cell lines as well as all 4 patient derived TNBC cells tested. Synergistic cell death and growth inhibition was observed in both Trop2 high-expressing and low-expressing cells, with data suggesting that the linker deconjugation and bystander effects of SG contribute to the efficacy in Trop2 low-expressing cells. Caspase-3/7 assays as well as cell death assays using cell death inhibitors demonstrated that the lethality of dual treatment is primarily mediated by apoptosis. Additionally, SG alone and in combination with Apo2L induced cycle arrest at the G2/M phase. Finally, xenograft models using HCC1806 bearing mice showed that dual treatment with SG and TRAIL agonists significantly inhibited tumor growth and caused a borderline significant benefit on survival with no toxicities noted for both drug treatments. Conclusions Combination treatment with SG and TRAIL agonists induces synergistic lethality in TNBC cells in vitro and inhibits tumor growth in vivo, suggesting a potential clinical benefit of the combination therapy in TNBC.

Background Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for metastatic HER2+ and HER2-low/ultralow breast cancer. It has shown impressive clinical activity for HER2+ brain metastases. We conducted preclinical brain metastasis experiments to understand T-DXd efficacy.Methods Nude mice were intracardially injected with either JIMT1-BR (HER2-2+) or SUM190-BR (HER2-3+) brain-tropic breast cancer cells and dosed with 3 or 10 mg/kg T-DXd or 10 mg/kg control-ADC, with endpoints of metastasis number and size, in both the metastasis prevention and treatment of established disease settings.Results In the JIMT1-BR model, T-DXd at both doses reduced metastasis number by 48% to 88% and size by 32% to 88%; a reduction of HER2 expression by lesions remaining at the experimental endpoint and heterogeneous T-DXd distribution were observed. A distinct dose effect was observed in SUM190-BR with the 3 mg/kg dose inhibiting size and number by 24% to 39% and 10 mg/kg by 72% to 79%; HER2 expression was maintained together with heterogeneous T-DXd distribution. In both models widespread reduced tumor Ki-67 was observed, while increased cleaved caspase-3 primarily costained with T-DXd. We used an in vitro model of the blood-brain and blood-tumor barriers (BBB/BTB) to ask how T-DXd crossed. Data demonstrated T-DXd endocytosis and transcytosis of brain endothelial cells partially reliant on the neonatal Fc receptor (FcRn). BTB transcytosis was accompanied by increased endothelial RAB11FIP5 expression in vitro and in vivo.Conclusions The data confirm T-DXd activity in HER2+ brain metastases and identify important correlates, including heterogeneous uptake, variable HER2 expression at endpoint, tumor cell cytotoxicity, decreased proliferation, and BTB transcytosis.

ABSTRACT Background Immunostimulatory effects of PARP inhibitors could increase sensitivity to immune checkpoint inhibitors. The previous Phase II trial (MEDIOLA) reported clinical benefits of durvalumab and olaparib (D + O) in patients with germline BRCA‐mutated (gBRCAm) HER2‐negative metastatic breast cancer. Yet, the clinical activity of D + O in germline BRCA wild‐type (gBRCAwt) triple‐negative breast cancer (TNBC) remains unknown. Methods This single‐arm Phase II study tested D + O in patients with metastatic TNBC. The primary objective was overall response rate (ORR). Secondary objectives were safety, disease control rate (DCR), progression‐free survival (PFS) and overall survival (OS). Based on gBRCA status, patients were assigned to either gBRCAwt or gBRCAm cohort and were treated with D (1500 mg iv q4w) and O (300 mg twice a day orally). Pretreatment fresh tissues and serial blood samples were collected for correlative studies. Results Fifteen patients (12 gBRCAwt and 3 gBRCAm) were enrolled. gBRCAm and gBRCAwt cohorts are reported as a combined dataset because of small sample size due to COVID‐19 and slow accrual. The median number of prior therapies was three (range 0–8). Among 14 RECIST‐evaluable patients (11 gBRCAwt and 3 gBRCAm), ORR was 28.6% (3 gBRCAm and 1 gBRCAwt). DCR was 64.3% (3 gBRCAm and 6 gBRCAwt). The median PFS and OS were 3.6 months (95% confidence interval [CI]: 1.8–5.7) and 10.7 months (95% CI: 5.9–38.9), respectively. There is one gBRCAm patient with ongoing durable PR (67.4+ months). There was no new safety concern. CD83 expression on Types 1 and 2 conventional dendritic cells in blood at baseline was low in the patients with PFS ≥ 4 months compared to those with PFS < 4 months. Conclusion Our study demonstrated modest clinical benefits of D + O with ORR of 28.6% in subsets of heavily pretreated TNBC. Further detailed classification of DCs to understand the predictive role of DCs and prospective validation in a large cohort is required. Trial Registration ClinicalTrials.gov identifier: NCT02484404

Tumor NOS2 and COX2 expression induced by IFNg and TNFa

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic that induces apoptosis in cancer cells while sparing the non-malignant cells in preclinical models. However, its efficacy in clinical trials has been limited, suggesting unknown mechanisms modulating TRAIL activity in patients. We hypothesized that TRAIL treatment elicits transcriptional changes in triple negative breast cancer (TNBC) cells that alter the immune milieu. RNAseq analysis of MDA-MB-231 cells along with validation in additional cell lines demonstrated that TRAIL induced cytokines such as CXCLs 1, 2, 3, 8,11 and IL-6, which are known to modify neutrophil function. Mechanistically, TRAIL dependent induction of the cytokines was predominantly mediated by death receptor 5, caspase-8 and the non-canonical NFKB2 pathway. These cytokines produced by TRAIL-treated TNBC cells enhanced chemotaxis of normal human donor isolated neutrophils. Using TNBC xenograft models, TRAIL induced activation of NFkB2 pathway, cytokine production and increased neutrophil recruitment into the tumors. Moreover, preincubation of neutrophils in supernatants from TRAIL-treated TNBC cells significantly impaired neutrophil function as measured by reduced respiratory burst and cytotoxic effect against TNBC cells. Transcriptomic analysis of neutrophils incubated with either TRAIL alone or supernatant of TRAIL-treated TNBC cells revealed increased expression of inflammatory cytokines, immune modulatory genes, immune checkpoint genes, and genes implicated in delayed neutrophil apoptosis. Functional studies showed that these neutrophils suppress T cell proliferation and augment Treg suppressive phenotype. Collectively, our study demonstrates a novel role of TRAIL-induced NFKB2-dependent cytokine production that promotes neutrophil chemotaxis and neutrophil-mediated immune suppression.