Citations

Abstract Neuroblastoma (NB) accounts for 10% of pediatric cancer-related deaths. High-risk NB is frequently metastatic at diagnosis and has a poor 5-year survival rate (<50%) despite aggressive treatment. GD2, a disialoganglioside glycolipid that is expressed in nearly all NBs, has been validated as a promising immunotherapy target. Although GD2-CAR-T cells have been clinically evaluated, their efficacy has been limited by poor tumor infiltration and the immunosuppressive tumor microenvironment (TME), highlighting the need for alternative immune-based strategies. With inherent capacity of macrophages to infiltrate tumors, phagocytose cancer cells, and modulate TME, they represent a promising alternative strategy for immunotherapy in NB. In this study, we developed and evaluated GD2-CAR-macrophages (GD2-CAR-Ms) as a novel therapeutic approach for NB. GD2-specific CAR constructs were designed, validated, and introduced into multiple human and murine monocyte/macrophage cell lines via lentiviral transduction. Fluorescent microscopy and flow cytometry confirmed a significant enhancement in the phagocytosis of GD2-high NB cells by GD2-CAR-Ms containing Hu3F8 single-chain variable fragment (scFv). A strong positive correlation was observed between GD2 expression levels on the target cells and phagocytosis efficiency of GD2-CAR-Ms, indicating that the phagocytic activity of GD2-CAR-Ms is antigen-specific. Anti-tumor efficacy was further evaluated in vivo using an immunocompetent Mycn-expressing NB non-genetically engineered mouse model (MYCN-NGEMM). Mice treated with GD2-CAR-Ms exhibited significantly reduced tumor burden and prolonged survival compared to control groups. Notably, treatment of mice bearing GD2-high tumors resulted in markedly improved survival, including one complete remission among ten treated animals, underscoring the therapeutic potential of GD2-targeted macrophage therapy. Histological analysis showed increased deposition of connective tissues and decreased tumor cells density, suggesting TME remodeling. Furthermore, immunohistochemistry reveals increased immune cell infiltration, particularly of macrophages, neutrophils and T cells, indicating a favorable shift in the immune TME from “cold” to “hot” following GD2-CAR-M treatment. Additionally, inhibition of tumor growth was also observed in our zebrafish NB model after GD2-CAR-Ms treatment, further supporting their therapeutic potential. Together, our findings demonstrate that GD2-CAR-Ms exhibit potent antitumor activity and reshape the tumor immune microenvironment, supporting their translational potential as a therapeutic strategy for high-risk NB. Citation Format: Ke-En Tan, Kok Siong Yeo, Cheng Zhang, Caleb Baker, Shyang Hong Tan, Alexis M. Sosic, Yat-Yuen Lim, Choong-Yong Ung, Cristina Correia, Stephanie F. Polites, Yi Lin, William A. Weiss, Hu Li, Shizhen Zhu. Engineering macrophages as a novel therapeutic approach for high-risk neuroblastoma [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 7810.

Abstract Background: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy with marked molecular heterogeneity, limited systemic treatment options, and poor prognosis. Chemoresistance and KRAS mutations remain major therapeutic challenges. Dysregulation of the Hippo pathway, particularly YAP/TAZ hyperactivation, drives CCA progression and resistance. TEAD, the essential transcriptional partner of YAP/TAZ, represents a promising target. IAG933 is a novel oral pan-TEAD inhibitor designed to disrupt YAP/TAZ-TEAD interactions. RMC-6236, a pan-KRAS inhibitor, has also gained attention. Combined TEAD and KRAS inhibition may overcome resistance and improve efficacy in CCA. Methods: We evaluated IAG933 in human (HuCCT1, RBE) and murine (SB1, FAC) CCA cell lines. Cells were treated with IAG933 alone or in combination with GemCis or RMC-6236. Cell viability assays were used to determine IC50 values and calculate combination indexes (CI). TEAD activity was assessed by luciferase reporter and qRT-PCR of YAP/TAZ target genes (CTGF, CYR61, NUAK2). Transcriptomic alterations were analyzed by RNA sequencing. In vivo efficacy was evaluated in syngeneic orthotopic and patient-derived xenograft (PDX) models. Results: IAG933 suppressed TEAD-dependent transcription (IC50 ≈ 500 nM) and downregulated YAP/TAZ target genes. Combination with GemCis or RMC-6236 produced synergistic effects (CI < 1) in all CCA lines. Transcriptomic analysis revealed activation of oxidative stress response pathways, particularly SOD2 upregulation. MitoSOX staining confirmed increased mitochondrial ROS after treatment. In vivo, IAG933 monotherapy suppressed tumor growth similarly to GemCis. Dual TEAD and KRAS inhibition achieved marked tumor regression and significantly delayed tumor regrowth after treatment cessation in KRAS-mutant PDX models. Conclusion: IAG933 effectively suppresses YAP/TAZ-TEAD signaling and inhibits CCA growth. While the combination with GemCis showed limited additional benefit due to strong single-agent efficacy, synergy with RMC-6236 produced durable antitumor effects, particularly in run-out studies, delaying regrowth in KRAS-mutant models. These findings highlight IAG933 as a promising therapeutic candidate targeting the Hippo-TEAD pathway, with potential benefit in KRAS-mutant CCA. Citation Format: Hidemi Nishi,Erik Jessen,Danielle M. Carlson,Amro M. Abdelrahman,Enis H. Ozmert,J. Pedro Fincatto Safi,Brandon A. Wilbanks,Shelby K. Yee,Jack W. Sample,Nathan W. Werneburg,Rory L. Smoot. TEAD inhibition by IAG933 as a novel therapeutic strategy for cholangiocarcinoma [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 3081.

Abstract Introduction: We aimed to characterize the preclinical pharmacokinetics (PK) of a series of 20 anticancer agents in highly immunodeficient female NOD scid gamma (NSG) mice to provide clearance and exposure data for agents under investigation by the NCI PDX Development and Trial Centers Research Network (PDXNet). Methods: The series of 20 anticancer agents (inhibitors of CDK4/6, PI3K-β/PI3K-δ, ATR, MEK1/2, PI3K, microtubule, EZH2, BCL-2, PARP, histone deacetylase, γ-secretase, FGFR, SHP2, and ERK1/2, as well as a SMAC mimetic) were administered to female NSG mice via IV, PO, or IP routes to characterize plasma exposures under conditions used for PDX efficacy testing. Serial plasma samples were collected 15, 30, 60, 120, 240, 360, 480, and 1440 minutes after dosing. Drug concentrations were quantified using validated LC-MS/MS assays. PK parameters were calculated using non-compartmental analysis. Results: The PK for each agent was determined, and the clearance and half-life values are listed in the table below. The PK metrics for Navitoclax could not be calculated. Due to higher metabolic rates, mice show faster PK processes. They generally had shorter half-lives and higher weight-normalized clearance than humans. Copanlisib, Navitoclax, and Trametinib were exceptions. Conclusion: These PK data are critical for understanding the antitumor activities of agents studied by the PDXNet and will aid investigators in developing new approach methodologies for preclinical safety studies in preparation for human clinical trials. Citation Format: Mohd Beshr Chama, Emily J. Koubek, Sarah A. Buhrow, Renee A. Schoon, Joel M. Reid. Pharmacokinetics of a series of anticancer agents in immunodeficient female NOD scid gamma mice [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 3156.

Abstract Background: Black men carry a disproportionate prostate cancer (CaP) burden and often experience significant psychosocial distress at the point of prostate cancer diagnosis (PPCD). Many report emotional shock, uncertainty, and limited access to culturally competent guidance, which can negatively affect treatment decisions and long-term survivorship. To address these needs, we developed the PPCD Virtual Reality Assistant (ViRA), an immersive, AI-enabled intervention co-designed with Black CaP survivors. ViRA delivers tailored psycho-oncology support, emotional guidance, and navigation of social determinants of health (SDOH) within virtual reality environments. This study evaluated the feasibility, acceptability, and usability of the PPCD ViRA (NCT06535802). Methods: ViRA was developed through a structured, seven-step co-design process with survivors, integrating mobile immersive technologies, SDOH navigation, and culturally grounded psycho-oncology content. Personalization was enabled through AI-driven predictive analytics and a recommendation engine. Alpha testing assessed initial usability and acceptability among 10 participants (seven team members and three Black CaP survivors). Beta testing with 24 Black men in Florida examined feasibility and preliminary efficacy. Results: A demonstration of ViRA is available (https://www.youtube.com/watch?v=1mI-HS5R6sk). Alpha testing indicated strong usability, positive emotional engagement, and clear promise for enhancing support at the PPCD. In Beta testing, participants varied in age; most were married (58.3%), held a bachelor’s degree (45.8%), were retired (45.8%), and had a family history of cancer (83.3%). ViRA use was associated with increased engagement and reduced distress across participants. Overall, 74% rated ViRA as “excellent,” while the remainder rated it as “good” or “very good.” More than 90% reported being “very satisfied,” with the rest indicating satisfaction. Conclusions: Findings demonstrate high feasibility, acceptability, and cultural relevance of the PPCD ViRA for supporting Black men at diagnosis. Lessons learned highlight the need for culturally embedded design, emotional timing, community co-creation, flexible delivery formats, and strong community partnerships to advance digital health equity. The refinement and larger-scale validation to establish clinical utility and readiness for implementation is ongoing (NCT07126548). Citation Format: Folakemi T. Odedina, Che Ngufor, Christopher Williams, Mary Ellen Young, Floyd Willis, Adam M. Kase, Arnold Merriweather, Emelina Asto-Flores, Dee M. Glaser-Boivin, Jada Melton, Monica L. Albertie, Michelle Fudge, Quincy Wimberly, Inclusive Cancer Care Research Equity (iCCaRE) Consortium, Prostate Cancer Transatlantic Consortium (CaPTC). Novel application of the iCCaRE consortium virtual reality assistant (ViRA) to support Black men at the point of prostate cancer diagnosis [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 6306.

Abstract Introduction: Black prostate cancer (CaP) survivors experience unique quality-of-life (QoL) and recovery challenges after treatment compared with their White counterparts. Smartphone-delivered mobile health interventions offer promising avenues for symptom tracking and lifestyle changes; but their feasibility, user engagement, and acceptability in this population remain unclear. This study assessed the feasibility, engagement, and preliminary impact of the Survivorship App for Ethnically Diverse Black Prostate Cancer Survivors (SAFE-CaPS), designed to improve self-monitoring behaviors and health outcomes. Methods: Nine Black CaP survivors (seven U.S.-born, one African-born, and one Caribbean-born) participated in a 12-week pilot study of SAFE-CaPS. The app provided daily prompts for symptoms (pain, sleep, fatigue, sexual function, anxiety, depression) and behavior tracking (physical activity, diet), brief self-management support, and physician alerts for severe symptom reports. Mental health (GAD-7 and PHQ-9) and QoL (FACT-P) were assessed at baseline and after 12 weeks. Feasibility was evaluated based on adherence rates (i.e., ≥70% of daily diary entries). Engagement and acceptability were assessed via app analytics and qualitative interviews on usability and cultural relevance. Participants were compensated up to $125 via Greenphire ClinCard. Surveys were analyzed with SPSS v29, and interviews with Atlas.ti v23. Results: Participants’ median age at diagnosis was 56 years; six had a positive family history of CaP, and four had undergone radical prostatectomy. Four participants met the feasibility threshold, and eight completed the study. Most daily entries reflected mild pain, fatigue, bowel and urinary issues, and generally good sleep. Several participants frequently reported severe sexual dysfunction, and most diary responses indicated <20 minutes of physical activity per day. Fruit/vegetable intake was low, with about half of daily responses showing 1-2 servings. At baseline, eight participants had minimal anxiety, while five had moderate depression. Overall, QoL improved from week 1 to week 12 in physical, emotional, and functional well-being, while social well-being declined over time. Interviews emphasized the app’s user-friendly design, ease of navigation, and acceptability as key strengths, with several participants highlighting its simplicity and ease of use, with recommendations to reduce repetitive items and address minor technical issues. Conclusions: SAFE-CaPS was feasible and well accepted. Sexual dysfunction, low physical activity, and moderate depression emerged as key concerns, heightening the need for integrated mental health, activity support, and stronger engagement strategies in future mHealth interventions. Citation Format: Gaurav Kumar, Parisa Ghasemi, Yan D. Zhao, Zsolt Nagykaldi, Kathleen A. Dwyer, Andrew G. McIntosh, Ernie Kaninjing, Mary E. Young, Dickey Sabrina, Daniel Morton, Opeyemi Bolajoko, Darla E. Kendzor, Motolani Ogunsanya. Feasibility of a survivorship app for black prostate cancer survivors: Results from a 12-week mHealth pilot study [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 6307.

Abstract Nearly 300,000 cancer patients are treated with fluoropyrimidine chemotherapy in the U.S. annually. Approximately one-third of patients experience severe and life-threatening toxicities, which can result in death. Deleterious genetic variants in DPYD, which encodes the rate-limiting enzyme of fluoropyrimidine catabolism (dihydropyrimidine dehydrogenase, DPD), have been correlated with severe toxicity in clinical studies. However, these variants explain only 10-30% of toxicity cases. Phenotypic measures of DPD function are attractive biomarkers of fluoropyrimidine toxicity risk with the potential to identify unknown causes of DPD deficiency. In this study, we compared two measures of DPD enzyme activity, blood plasma dihydrouracil to uracil ratio (UH2:U) and direct measurement of DPD activity in peripheral blood mononuclear cells (PBMCs) using 204 subjects with comprehensive DPYD genotype data. DPD PBMC measurements showed higher overall inter-individual variation compared to UH2:U ratios. Low correlation between UH2:U and PBMC measurements were noted for matched samples taken from the same subject. As expected, DPD metabolites (U and UH2) correlated with UH2:U ratio; however, no correlation was noted between U or UH2 levels and the PBMC DPD activity. Furthermore, when data were analyzed by genotype, no correlations were noted between UH2:U and PBMC DPD activity. We observed the expected decrease in UH2:U ratio for carriers of the four clinically tested DPYD variants and identified two novel variants associated with a significantly decreased UH2:U ratio. To further investigate the impact of rare genotypes and previously identified DPYD haplotypes on the UH2:U ratio, additional cohorts of 1994 and 500 subjects, enriched for specific genotypes, were utilized. Our results suggest that phenotyping may have limited validity as a single test when predicting DPD deficiency at an individual level and call into question the often-reported belief that PBMC DPD activity represents the "gold standard" for identifying DPD deficiency. Additional studies are needed to investigate correlations between phenotypic measures and 5-FU toxicity in patients, potentially as secondary biomarkers in conjunction with genetic tests. Citation Format: Brianna Bembenek, Kelly Bouchonville, Carlo Largiadèr, Steven M. Offer. Comparative analysis of phenotypic markers of DPD activity as biomarkers of 5-FU toxicity [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 3135.

Abstract Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) is the rate-limiting enzyme in the catabolism of the widely used chemotherapeutic drug 5-fluorouracil (5-FU). Genetic variations in DPYD are predictive biomarkers of 5-FU toxicity. One such biomarker, rs75017182 (the causal allele linked to the “HapB3” haplotype), has been suggested to promote alternative splicing of DPYD, leading to expression of an inactive proteoform. However, carriers of rs75017182 exhibit only moderately increased risk of 5-FU toxicity and modestly decreased ex vivo DPD activity compared to carriers of another well-studied splice variant, rs3918290 (*2A). We hypothesized that, unlike *2A, the rs75017182 variant does not cause obligate alternative splicing but instead promotes partial alternative splicing. To test this, we generated dual-fluorescent minigene reporter constructs containing either the G (wildtype) or C (variant) allele. In our minigene system, alternative splicing was elevated in cells transfected with C-containing vectors via flow cytometry, though levels were lower than those observed in a parallel *2A model. To investigate contributions of other variants in LD with rs75017182, we expanded the reporter to include additional relevant genomic regions. The analyses were complemented by the study of in vivo splicing in cells engineered to harbor various combinations of variants and in lymphoblastoid lines carrying specific genotype combinations. Overall, our findings demonstrate that rs75017182-C promotes only partial alternative splicing, eliciting a modest decrease in DPD activity and explaining its comparatively weak association with severe 5-FU toxicity. Additional variants in LD have a minimal impact on splicing and 5-FU sensitivity. Citation Format: Lauryn Allyn Hahn, Ryan Schwartz, Hannah Marie Krause, Lulu Jiang, Brianna Bembenek, Kelly Bouchonville, Steven M. Offer. Partial alternative splicing in carriers of DPYD rs75017182 explains modest association with severe 5-FU toxicity to 5-FU [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 3137.

Abstract Background and Aims: Colorectal cancer is a leading cause of cancer mortality and most rectal cancers are mismatch repair proficient (pMMR), making them largely resistant to PD-1 inhibitors (PD1i). While PD1i achieves excellent complete response rates in MMR-deficient tumors, these represent <5% of rectal cancers. For the remaining 95% of patients, effective immunotherapy strategies are urgently needed. We evaluated two high-LET radiation approaches to prime pMMR rectal cancers to PD1i and enhance local control: 1) Diffusing alpha emitter Radiation Therapy (DaRT) implants, and 2) LET-optimized (Bragg Peak) protons + ATM inhibitor. An ATM inhibitor was evaluated with protons to evaluate whether it could produce a more alpha/carbon-like effect given the lower comparative LETd achievable in clinical treatment plans. Methods: In vitro proton irradiation of HCT116, HT29, SW480, and CT26 was performed as previously with dose averaged LET (LETd) values of 2.2 keV/um for ENT and 7.0 keV/um for BP protons. Female Balb/C mice were subcutaneously inoculated with 1×10^6 CT26 cells on one flank and 1×10^5 cells on the contralateral flank to establish primary and secondary (abscopal) tumors, respectively. PD1i monoclonal antibody (RMP1-14 Bio X Cell) was administered i.p. 100ug every 72 hours for 4 total doses. The ATM inhibitor AZD1390 was delivered via oral gavage at 20 mg/kg, PO 1 hour prior to radiation. For in vivo studies, radiation was delivered using a PXI SmART small animal irradiator with opposing lateral beams (225 kVp, 20 mA, 0.3mm Cu filter). Proton irradiation plans were produced as previously described. We used mass cytometry by time of flight (CyTOF) using the TME CD45 lymphocyte subpopulations based on multiple cell markers. Result: In our preliminary data we demonstrate that both DaRT and BP protons+ATMi synergize with PD1i to dramatically increase complete response rates at both primary and abscopal tumors by increasing DNA damage, activating innate immune pathways, and reducing immunosuppression within the tumor microenvironment. Critically, this effect was observed in a pMMR model which did not respond to PD1i or conventional X-rays+PD1i, highlighting the innovation and potential impact of this work. Conclusion: DaRT and BP protons ATMi prime pMMR colorectal cancer to PD1i, and all elements are clinically translatable. Citation Format: Cameron M. Callaghan. Particle therapy, ATM and PD-1 inhibition for pMMR rectal cancer [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 2569.

Abstract Background: Diffuse pleural mesothelioma (DPM) is a highly aggressive malignancy with limited treatment options and poor prognosis. Although immune checkpoint inhibitors have improved outcomes, particularly for non-epithelioid subtypes, there remains no approved targeted therapy for mesothelioma. EGFR and MET are receptor tyrosine kinases frequently overexpressed in DPM, suggesting susceptibility to targeted antibody therapy. Amivantamab is a bispecific EGFR/MET antibody, originally developed for EGFR-mutant lung cancer, that blocks growth signals and engaging immune mechanisms. Given the high levels of EGFR and MET expression in mesothelioma, we evaluated the therapeutic potential of amivantamab in preclinical models. Methods: EGFR and MET transcript levels in DPM were analyzed using TCGA. Eight human mesothelioma cell lines were assessed by Western blotting and flow cytometry. Amivantamab binding, internalization, and signaling inhibition were examined using flow cytometry, confocal microscopy, and ligand-stimulated phosphorylation assays. Cytotoxicity and immune-effector activity were quantified using PBMCs, NK cells, and monocytes from healthy donors, along with an ADCC reporter assay. In vivo efficacy was tested in a DPM patient-derived xenograft (PDX) model in NOD/SCID-γ (NSG) mice supplemented with human NK cells and treated with amivantamab or control IgG. Results: TCGA analysis showed frequent EGFR/MET co-expression in DPM. Mesothelioma cell lines expressed higher EGFR and MET levels compared with mesothelial cells. Amivantamab strongly bound both receptors, induced receptor internalization, and inhibited EGF- and HGF-stimulated phosphorylation of EGFR, MET, and downstream AKT/ERK signaling. Direct cytotoxicity was minimal; however, the addition of PBMCs or NK cells resulted in robust, dose-dependent tumor cell killing consistent with antibody-dependent cellular cytotoxicity (ADCC). Reporter assays demonstrated 7-11-fold Fcγ receptor activation in tumor cells compared with ∼2-fold activation in non-malignant mesothelial cells. Co-culture with monocytes revealed amivantamab-induced trogocytosis, evidenced by loss of EGFR and MET from tumor-cell membranes. In the DPM PDX model, amivantamab produced 89.1% tumor-growth inhibition (TGI) relative to controls (P < 0.0001), with no overt toxicity observed in treated mice. Conclusions: Dual EGFR/MET targeting with amivantamab produced potent antitumor effects in mesothelioma through coordinated receptor-signaling blockade, ADCC, and monocyte-mediated trogocytosis. These results support amivantamab as a promising targeted therapeutic strategy for EGFR/MET-positive DPM, particularly epithelioid subtypes that currently derive limited benefit from immunotherapy. Citation Format: Shinichiro Suzuki, Kaushal Parikh, Ezequiel Tolosa, Kuan-Li Wu, Jennifer Ayers-Ringler, Lin Yang, Katherine E. Smith, Farhad Kosari, Aaron S. Mansfield, . Enhancing antibody-dependent cellular cytotoxicityin mesothelioma through concurrent EGFR and MET targeting withamivantamab [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 5547.

Abstract Background: Most colorectal cancer (CRC) arises from polyps and is mainly prevented by polypectomy. The most important polyps to manage with colonoscopy are those with highest CRC risk- namely, advanced polyps (> 1cm, villous histology or high-grade dysplasia (HGD). Yet, 48% of advanced polyps recur within 1 to 3 years of removal, and up to 5% of advanced polyps under surveillance still progress to CRC. We performed this pilot study to investigate molecular and microenvironment heterogeneities of polyps and how they might impact their clinical behavior. Methods: GeoMx spatial transcriptomics was performed on FFPE tissues from three different polyp outcome phenotypes (POPs) including the polyp that does not recur (POP-NR), that recurs following polypectomy but cured by colonoscopy (POP-R) or the polyp despite polypectomy develops CRC at the polypectomy(ies) site (POP-CRC). Normal colon and polyp with low or HGD from the index polyp were assessed from 6 patients with POP-NR, 9 with POP-R and 12 with POP-CRC with a minimum of 2 follow up colonoscopies at 3-year intervals. Epithelium was identified as PanCK positive, and stroma identified as PanCK negative and positive nuclear staining. Cell type deconvolution was implemented using single-cell adult human intestinal tract catalogue (Elmentaite et al., https://www.gutcellatlas.org/). Differential gene expression (DEG), cell type abundance and functional enrichment analyses was performed using linear mixed effects model, and observations with p-value < 0.05 and log2FC >= |1| are reported. Results: The greatest number of DEGs were identified in stroma of the index POP-CRC compared to POP-NR polyps (n = 17 down and 11 upregulated genes), followed by epithelium of the index POP-CRC vs POP-NR polyps (n = 10 down and one upregulated gene(s)). Between the index POP-CRC and POP-R, epithelium showed downregulation of 7 genes, and upregulation of no genes. In stroma two genes were down and none upregulated. Four genes were downregulated in stroma of the index POP-R vs POP-NR polyp and 3 in epithelium, and one gene was upregulated in stroma and another in epithelium. MZT2B was upregulated in stroma of both the index POP-R (log2FC = 1.09, p-value = 0.0014) and POP-CRC (log2FC = 1.29, p-value = 0.0001) and has been implicated as a prognostic marker associated with worse prognosis in certain cancers. IgM and IgA plasma cells, proximal progenitors, MMP9+ inflammatory macrophages and myofibroblasts were found to be downregulated in epithelium of index POP-CRC and POP-R compared to POP-NR polyps; while microfold cells were downregulated in stroma of index POP-CRC and POP-R compared to POP-NR polyps. Conclusions: The stromal microenvironment and less so, epithelial features present in the index polyp differ based on a polyp’s future clinical behavior. The polyp-immune interaction warrants further study as a potential prevention target against polyp progression. Citation Format: Mrunal Dehankar, Lisa A. Boardman, Daniel O'Brien, E. Aubrey Thompson, Jennifer M. Kachergus, Ji Shi, Alexej Abyzov, Milovan Suvakov, Rondell P. Graham, Chen Wang. Stromal immune composition significantly contributes to adenomatous polyp recurrence or progression to cancer [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 4018.