Citations

Abstract Background: Despite the decline in overall mortality and incidence of cancer in the US population, the burden of cancer is still high, especially in underserved and under-researched populations. A major contributor to poor cancer outcomes is the absence of dedicated efforts utilizing scientifically rigorous approaches and implementation strategies to optimize participant enrollment and accrual in clinical trials. The Connecting Patient Populations to Clinical Trials (CP2CT) program implements innovative multilevel interventions to enhance clinical trial awareness and optimize referral pathways that facilitate patient enrollment. The CP2CT Data, Evaluation, and Coordinating Center (DECC) supports its data and evaluation activities, and coordinates a learning collaborative towards mitigating the key barriers of cancer burden in all populations. Methods: Using an implementation science-informed approach, the DECC deployed coordinated strategies over three years: (1) administrative structuring through streamlined governance, centralized reporting, and stakeholder integration; (2) data standardization via Common Data Elements (CDEs), a cross-network REDCap system, and a multi-institution Data Transfer Agreement (DTA); (3) evaluation infrastructure through a Network Logic Model, evaluation plan, standardized constructs, and a Process Evaluation Plan with tools; (4) learning supports through an internal website and expanded Speaker Series; and (5) site-level implementation facilitation through structured visits. Results: In collaboration with the CP2CT Network and NCI, the DECC’s achievements span four domains: (1) Administrative: built infrastructure, deployed centralized reporting platforms, coordinated key meetings, and strengthened community integration. (2) Data: standardized collection, secured network-wide data sharing through the DTA, enabled harmonized multi-site reporting, and advanced groundwork for interoperability and scientific value. (3) Program Evaluation: linked CP2CT activities to measurable outcomes through a Network-wide Logic Model, guided evaluation, established shared evaluation language, and launched a transferable Process Evaluation framework. (4) Learning Collaborative: developed a centralized resource hub, expanded the Speaker Series, and advanced authorship transparency with the CP2CT Publication Policy. < Conclusion: The CP2CT DECC has established a sustainable, scalable infrastructure that integrates administrative coordination, standardized data collection, robust program evaluation, and a collaborative learning environment. These efforts enhance clinical trial awareness, optimize referral pathways, and provide a transferable model for improving participant enrollment and scientific rigor across national research networks, ultimately addressing disparities in cancer outcomes. Citation Format: Laura E. Lectora, Cristina J. Orozco, Holly A. Thorson, Timethia Bonner, Robert R. Freimuth, Jennifer G. Le-Rademacher, Folakemi T. Odedina. Building a national network coordination center for clinical trials: Early implementation outcomes from the CP2CT DECC [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 899.

Abstract Introduction: The prostate cancer (PCa) tumor microenvironment (TME) is immunosuppressive and resistant to immune checkpoint blockade (ICB). Based on multi-omic single cell correlatives of response to neoadjuvant Fc-enhanced (FcE) αCTLA-4 in high-risk localized PCa (NCT04301414), we explored how modulating the balance between regulatory T cells (Tregs) and dendritic cells (DCs) in the PCa TME affects sensitivity to ICB. Methods: We leveraged three single cell transcriptomic atlases of PCa to assess how Tregs and DC frequencies are dynamically regulated during PCa progression. To investigate responses to Treg depletion (via FcE-αCTLA-4) alongside DC expansion (via Flt3L-Ig) and stimulation (via STING agonist ADU-S100) in PCa, we employed the castration-sensitive MycCaP PCa model and 45-parameter spectral flow cytometry. To investigate novel direct mechanisms of DC stimulation by FcE-αCTLA-4 via Fcγ receptor (FcγR) engagement, we optimized reductionist in vitro assays involving bone marrow-derived DCs (BMDCs) from wild-type (WT) mice or mice deficient in activating FcγRs (Fcer1g-/-) or inhibitory FcγRIIb (Fcgr2b-/-). To validate this effect in vivo we established a tumor antigen-specific T cell priming assay with both flow cytometry and ex vivo 2-photon live cell imaging readouts. Results: In three independent single cell transcriptomic PCa atlases, we find cDC2 frequencies are significantly decreased in advanced PCa while effector Tregs (TNFRSF9+) increase in proportion. Hypothesizing that excessive Treg function and DC insufficiency drive ICB resistance in PCa, we find in vivo DC expansion (Flt3L-Ig) prior to hormonal therapy, Treg depletion (FcE-αCTLA-4), and in situ DC stimulation (ADU-S100) drives robust control of established MycCaP tumors, with 87% of animals tumor-free 40-days post-treatment (27/31). Using 45-parameter spectral flow cytometry we find FcE-αCTLA-4 drives DC activation prior to Treg depletion in the TME, supporting a novel direct mechanism of DC modulation by FcE-αCTLA-4. In vitro, we find cell-associated FcE-αCTLA-4 is sufficient to drive BMDC maturation in an FcγR-dependent manner. In vivo, FcE-αCTLA-4 augments DC-mediated T cell priming in an FcγR-dependent manner. Ongoing experiments are investigating how FcE-αCTLA-4 shapes DC-T cell interactions via FcγR engagement and how DC/Treg axis modulation can be optimized to improve long-term curative response rates in the MycCaP model. Conclusions: DC insufficiency and effector Treg differentiation are hallmarks of advanced PCa. Enhancing DC number and function concomitant with Treg depletion can drive effective antitumor immunity in a pre-clinical PCa model. Direct DC modulation via FcγR engagement represents a novel mechanism of response to CTLA-4-targeted ICB. These findings will inform ongoing translation of FcE-αCTLA-4 agents and development of novel immunotherapy strategies for PCa. Citation Format: Jessica C. Hill, Kade R. Copple, Collin Jugler, Phuong Nguyen, Nilika Bhattacharya, Jessica N. Lancaster, Casey R. Ager. Rewiring the dendritic cell: Regulatory T cell axis sensitizes prostate cancer to immunotherapy [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 166.

Abstract Backgroud. Breast cancer (BC) is the most common and deadly cancer in women worldwide. Emerging evidence highlights the role of gut microbiota in modulating breast cancer risk, treatment response, and recurrence through various mechanisms, including the production of biologically active compounds and metabolites. These non-viable microbial products and metabolic byproducts from probiotic fermentation, known as postbiotics, exert beneficial effects on the host without the need for live microorganisms. Postbiotics derived from Lacticaseibacillus species represent a novel class of therapeutics with potential anti-cancer properties. In this study, we investigated the therapeutic effects of an innovative postbiotic product (iPB), developed through sequential fermentation of L.paracasei NPB01 and L.rhamnosus GG, in BC experimental models. Methods. The following cell lines were used to represent main BC subtypes: MCF7 cells (ER+/HER2), MDA-MB-231 (triple negative breast cancer), SKBR3 (HER2+). MCF-10A (normal breast epithelial cells), Caco-2 (enterocytes), and peripheral mononuclear blood cells (PBMC) were used as control. Cell viability was assessed by colony formation assay. Apoptosis was evaluated using Annexin V/7-AAD staining, HLA class I surface expression by flow cytometry, and cancer cells migration by wound healing assay. Results. iPB exposure resulted in >50% colony formation reduction in MCF7, >30% in MDA-MB-231 and >40% in SKBR3 cells starting from 0.5 mg/ml for 72 h (p<0.01). iPB increased early and late apoptotic cell rate in all BC cell lines starting from 0.5 mg/ml for 72 h. On the contrary, iPB exposure up to 5 mg/ml for 120 h did not affect cell viability in control cells (MCF-10A, Caco-2, PBMC). 1.20 to 1.30 fold increase in HLA class I expression was observed in all BC cell lines after the exposure with iPB starting from the dose of 0.5 mg/ml for 72 h. A less intense HLA class I expression increase was observed in control cells after the iPB exposure. Cell migration process and inflammatory cytokines response were inhibited by the iPB exposure in all BC cell models. Conclusions. iPB reduces cell viability and cell migration in all main BC phenotypes. These effects parallel with HLA class I surface expression increase in all BC cell phenotypes, potentially enhancing immunogenicity. These findings suggest that iPB may represent a promising novel agent in BC treatment and prevention. Citation Format: Roberto Berni Canani, Chiara Luongo, Laura Pisapia, Franca Oglio, Roberta Di Santillo, Alessia Gaeta, Chiara Scocco, Marco Michelini, Vittoria Mauriello, Alessia Cadavere, Camilla Messuri, Saranya Chumsri, Dawn Mussallem. Postbiotic based on sequential fermentation of L.paracasei NPB01 and L.rhamnosus GG exerts antitumor activities against breast 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 312.

Abstract Background: Early-onset colorectal cancer (EOCRC) is rapidly increasing, with projections that by 2030, one in ten colon cancers will occur in individuals under 50. Unlike hereditary syndromes, most EOCRC cases are sporadic, implicating environmental and aging-related mechanisms. Accelerated biological aging, characterized by telomere attrition, oxidative stress, and senescence-associated inflammation, is a defining feature of EOCRC. Micro- and nanoplastics (MNPs) can accumulate in the gut, induce oxidative stress, and damage DNA. These processes mirror hallmarks of aging, suggesting that chronic MNP exposure may accelerate colonic epithelial aging and promote EOCRC initiation. Methods: To test this hypothesis, we used patient-derived human colon organoids from normal and polyp tissues. Apical-out organoids, which expose the luminal surface to the environment, were treated with defined polyethylene-derived microplastics (1.7-2.2 μm) and nanoplastics (0.04-0.06 μm) at 0, 1 and10 μg/mL for up to 72 hours. We assessed viability, oxidative stress, senescence markers, and inflammatory cytokines. Telomere length will be quantified by qPCR, and cytokine profiling was performed using Olink proteomics. Results: Live/Dead assays revealed minimal cytotoxicity at 1 μg/mL, while nanoplastics induced greater cell death and oxidative stress at 10 μg/mL. Preliminary data suggest that nanoplastic exposure leads to telomere shortening. Moreover, gene expression analyses showed that nanoplastics triggered stronger mitochondrial and redox stress responses than microplastics, consistent with higher reactivity of smaller particles. Additional experimental groups will be included to validate and expand upon these preliminary findings. Conclusions: Although preliminary, these data point to potential links between MNP exposure and early aging-associated stress pathways in the colon epithelium. Continued refinement of this organoid model, together with expanded sample sizes and multiomic analyses, will be essential for determining whether these early signals represent meaningful contributors to EOCRC risk. Funding: Individualizing colorectal cancer patient care using the host and tumor telomere phenotype (RO1 CA204013), Curtiss Fund (92541775), C-SiG Core(s): Epigenomics & Spatial Biology Core, and Clinical Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567) Citation Format: Zahra Heydari, Gobinda Sarkar, Lisa A. Boardman. Modeling micro- and nanoplastics-induced colon aging in organoids to unravel pathways leading to early-onset colorectal 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 746.

Abstract Maternal obesity has been epidemiologically linked to an increased risk of sporadic colorectal cancer (CRC) in offspring, the third most prevalent cancer worldwide. This association underscores the lasting influence of early-life exposures on long-term health and disease susceptibility. Intestinal stem cells (ISCs), the long-lived cells that sustain epithelial renewal and often serve as the origin of intestinal cancers, are thought to play a central role in mediating this elevated cancer risk. However, how maternal obesity shapes the early-life programming and maturation of ISCs in their offspring remains poorly understood. Using mouse models of diet-induced obesity, we show that offspring exposed to a maternal high-fat Western diet (HFD) during pre- and postnatal development exhibit increased colonic proliferation, enhanced stem cell self-renewal, and a hypermetabolic state that persists into adulthood, even after dietary normalization. Alongside changes in stem cell properties, we observe a significant shift in epithelial cell composition, characterized by an increase in cells of secretory lineage at the expense of absorptive enterocytes, and these changes endure into adult life. Additionally, these changes are accompanied by an increased tumor burden in the loss of Apc heterozygosity model. Our data indicate that IL-17a, a pro-inflammatory cytokine, is critical in mediating these changes. Specifically, receptor IL-17RA/C expression is significantly upregulated in ISCs and secretory cells in maternal HFD-exposed offspring. Administration of IL-17a to intestinal organoids demonstrates sufficiency by mimicking the maternal obesogenic phenotype, indicating that immune-epithelial interactions influence ISC function and may be a driver of durable molecular patterning. These findings emphasize the long-term consequences of maternal HFD exposure on intestinal stem cell activity and epithelial composition, and possibly contribute to a higher risk of CRC in offspring later in life. Citation Format: Gourab Lahiri, Karla Mullen, Yesenia B. Millan, Swathi Sankar, Dominic R. Saiz, Thomas H. McDermott, Madeline Blatt, Abhigyan Shukla, Khashayarsha Khazaie, Miyeko D. Mana. Maternal obesity reprograms intestinal stem cells to elevate colorectal cancer risk in offspring [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 841.

Abstract Background: Multidisciplinary research networks often face challenges in harmonizing metrics and measures across participating sites, limiting the ability to aggregate data and generate generalizable insights. To address this barrier within the Connecting Patient Populations to Clinical Trials (CP2CT) Network, the Data, Evaluation, and Coordinating Center (DECC) coordinated the establishment of a unified framework that supports comparable evaluation and enhances the scientific impact of network-wide activities. Methods: Consensus was developed through a structured, iterative, and collaborative process: (1) drafting initial constructs, metrics, measures, and benchmarks informed by Network site materials and relevant literature; (2) soliciting qualitative and quantitative feedback from Network sites via Basecamp, an innovative online collaborative workspace for construct development; (3) conducting open dialogue sessions followed by systematic review and integration of site feedback; and (4) refining all elements through repeated feedback cycles until no further modifications were requested. Each iteration strengthened the clarity, coherence, and scientific precision of the final constructs. Results: A total of seven constructs were incorporated into the consensus-development process: clinical trials referral, clinical trials accrual, participants’ awareness of clinical trials, participants’ knowledge of clinical trials, providers’ awareness of NCI-supported clinical trials, providers’ engagement with NCI-supported clinical trials, and providers’ referral to NCI-supported clinical trials. For each construct, the Network established a conceptual definition (broad description of the construct), an operational definition (specification of how the construct is measured or observed), benchmarks (standards for assessing performance), metrics (quantitative indicators of performance), and measures (tools used to quantify inputs, processes, or outcomes). Common measures were developed for two constructs—clinical trials accrual and participants’ knowledge of clinical trials. Although full consensus was not achieved across all four Network sites for every construct, at least three sites reached consensus for the remaining five constructs. Conclusion: This consensus-building initiative resulted in the development of a unified, scientifically grounded framework. By harmonizing key elements related to clinical trial referral, accrual, awareness, knowledge, and provider engagement, the Network has established foundational tools that enable cross-site data comparability and facilitate more rigorous assessment of efforts to connect diverse patient populations to clinical trials. This framework positions the Network to inform strategies that improve equitable clinical trial participation. Citation Format: Folakemi T. Odedina, Jennifer Le-Rademacher, Robert Freimuth, Cristina Orozco, Laura Lectora, Timethia Bonner, Holly Thorson, Connecting Patient Populations to Clinical Trials(CP2CT) Program Evaluation Work Group, Connecting Patient Populations to Clinical Trials(CP2CT) Steering Committee. Development of and consensus building towards shared metrics, measures and benchmarks for the connecting patient populations to clinical trials (CP2CT) [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 860.

Abstract Background: Primary Cardiac Lymphoma (PCL) is an exceptionally rare malignancy. While clinical case reports have postulated an association with human immunodeficiency virus (HIV), large-scale epidemiological data corroborating this link are limited. Objective: To determine whether HIV is associated with increased prevalence of PCL in a large, nationally representative sample of US hospitalizations. Methods: We performed a retrospective, cross-sectional analysis using the Healthcare Cost and Utilization Project National Inpatient Sample from 2016 to 2019, representing approximately 35 million unweighted hospitalizations. Hospitalizations were identified using a proxy definition for PCL, requiring ICD-10-CM codes for both cardiomyopathy (I42.*) and extranodal non-Hodgkin lymphoma (i.e., C83.39, C85.99). HIV status was identified using codes B20-B24 and Z21. We compared the prevalence of PCL in hospitalizations with versus without HIV and calculated odds ratios using Fisher’s Exact Test, reporting corresponding 95% confidence intervals (CI) and p-values. Results: We identified 569 hospitalizations meeting our operational definition for PCL out of 34,955,252 total discharges. The prevalence of PCL was significantly higher among hospitalizations with HIV (6.2 per 100,000) compared with those without HIV (1.6 per 100,000; p < 0.0001). HIV was associated with a 3.86-fold increased odds of PCL (OR: 3.86; 95% CI: 2.23-6.70; p < 0.0001). Conclusion: In this nationwide analysis of 35 million hospitalizations, HIV was strongly associated with a higher prevalence of PCL. Hospitalizations with HIV had nearly 4-fold higher odds of PCL, as defined by co-occurrence of cardiomyopathy and extranodal lymphoma, compared with hospitalizations without HIV. This population-level finding evinces the association previously suggested in clinical case reports. Citation Format: Omar Hozayen, Jay Hozayen, Benjamin Behers, Christoph Stephenson-Moe, Maha Hameed, Matthew Miller, Laura De Jesus Herrera, Anas Abu Jad, Rheiner Kammer, Mohab Idriss, Ahmed Aboutaleb, Bashar Roumia, Patricia Riano, Nicolas Riveros Neira, Brooke Hartenstein, Robert Taylor, Manuel Rosario Espinal, Brett M. Behers, Alya Hozayen, Mohamed Ibrahim, Karen Hamad. Primary cardiac lymphoma and HIV: A nationwide analysis of hospitalizations [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 215.

Abstract Introduction. This study aimed to characterize the population pharmacokinetics (PopPK) of nab-paclitaxel following the administration of the nano-immunoconjugate nab-paclitaxel-bevacizumab to patients with unresectable stage IV melanoma or gynecological cancers (NCT02020707). The core objective was to characterize the population mean drug concentration-time profile, understand the variability in drug concentrations and identify factors that explain differences in paclitaxel plasma clearance. Also, we sought to explore the impact of the nano-immunoconjugate formulation on paclitaxel clearance. Methods. Using Pumas AI - an advanced pharmacokinetic software program, integrating Machine Learning methods - a PopPK analysis was conducted using concentration-time data collected from 29 subjects, (681 concentration measurements). Patients received 75 - 175 mg/m2 (total dose, 160 - 360 mg). Data were fitted to a 2-compartment model based biphasic decline observed in plasma concentration following intravenous administration. A critical requirement for the model was the inclusion of saturable elimination to accurately describe the drug’s disposition. A comprehensive modeling workflow was implemented, starting with base models (mixed vs. non-linear clearance), followed by the sequential addition of covariates (Age, Sex, BSA, Tumor, Cycle). The Parsimony Principle was applied to select the most appropriate model. Results. Population estimates for paclitaxel clearance and volume of distribution were 41.7 L/hr and 312 L, respectively. The analysis found paclitaxel clearance higher when compared with published data for nab-paclitaxel alone (21.1 or 25 L/h/m2; Sparreboom et al, CCR 11:4136, 2005 and Ando et al, CCP 69:457, 2012). A covariate model incorporating BSA and Gender is the best. For every 2 m2 increase in BSA, linear clearance (CL) increases by 6.9%. Females have 16.6% lower CL than males, which successfully characterized systematic differences in PK between subgroups of subjects. Conclusion. The administration of nab-paclitaxel via the nano-immunoconjugate formulation led to increased clearance for paclitaxel consistent with known clearance mechanisms for therapeutic antibodies. The differences in drug clearance among patients were primarily attributable to covariates BSA and gender. These findings are crucial for identifying safe and effective dosing regimens and informing future clinical simulations. Citation Format: Mohd Beshr Chama, Matthew Stephen Block, Vera J. Suman, Joel M. Reid. Population pharmacokinetics of nab-paclitaxel following administration of a nano-immunoconjugate with bevacizumab [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 301.

Abstract Introduction: Attending to survivorship including distress in the contexts of social drivers (SDH) is critical but lacking. In response, this novel research on Black CaP survivors (CaPS) aims to measure SDH distresses and assess utility of a digital intervention to inform survivorship studies, practice and outcomes. Method: Informed by the Science of Survivorship, and our pilot study with multisectoral stakeholders, we assessed SDH and acceptability/utility of a digital Survivorship Care (SC) Toolkit. SCToolkit is a digitized whole-person care with guidance from multisectoral stakeholders e.g., clinicians and survivors. SCToolkit includes: ASCO informed treatment summary template for diagnostics, treatments, side effects, care team, genetics, and comorbidities, and patient active guide on survivorship concerns, provider communication, health advisories, survivorship care booklet, SDH FINDHELP resource, and survivorship videos. SCToolkit was delivered via survivors’ personal REDCap file, and can be uploaded to their EMR patient portal for easy-to-use survivorship roadmap accessible on smartphones, laptops, and computers. Motivational Interviewing was provided via Zoom to facilitate digital efficacy and SCToolkit use. Descriptive analyses were conducted using SAS. Citation Format: Kimlin Ashing, Floyd Willis, Christopher Williams, John McCall, Gaole Song, Douglas Adu-Fokuo, Erika Galdamez, Fornati Bedell, Cassandra N. Moore, EWAN COBRAN, Che Ngufor, Kathleen J. Yost, Timethia J. Bonner, Getachew Dagne, Arnold Merriweather, Ernest T. Kaninjing, Rotimi Oladapo, Roxana S. Dronca, Folakemi T. Odedina. Examining contextual distress and utility of a digital survivorship care toolkit [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 880.

Abstract Cholesterol has long been viewed as a structural component of cellular membranes, yet its role in DNA damage response remains poorly defined. Here, we show that ionizing radiation (IR) induces broad transcriptional upregulation of cholesterol biosynthesis, transport, and storage pathways, leading to sustained intracellular accumulation of cholesterol. BODIPY-cholesterol imaging, Filipin III staining, and quantitative subcellular fractionation confirmed selective nuclear enrichment of cholesterol following IR, coinciding with extensive chromatin remodeling. Proteomic profiling of cholesterol-interacting proteins revealed a strong enrichment of chromatin-associated factors, suggesting a previously unrecognized lipid-chromatin interface in irradiated cells. Functionally, cholesterol accumulation promoted chromatin compaction and repressive histone modification patterns, impairing DNA damage sensing and checkpoint activation despite increased underlying DNA lesions. These alterations facilitated aberrant mitotic entry, formation of cytoplasmic chromatin fragments (CCFs), and activation of cGAS-STING-NF-κB signaling. Cholesterol exposure ultimately diverted damaged cells toward a senescent fate, marked by Lamin B1 loss, p21 induction, and a robust senescence-associated secretory phenotype (SASP) enriched for IL-1 and TNF family cytokines. In vivo, dietary cholesterol exacerbated radiation-induced inflammation and weakened systemic anti-tumor immunity. Transcriptomic analyses of immunotherapy-treated patients revealed that tumors enriched for cholesterol import and senescence signatures were associated with poor response to PD-L1 blockade and worse survival. Together, these findings identify a cholesterol-chromatin-senescence axis that links metabolic remodeling to defective DNA damage signaling and immune suppression after radiation, highlighting cholesterol metabolism as a potential therapeutic vulnerability in cancer therapy. Citation Format: Yiqun Han, Yaobin Ouyang, Shouhai Zhu, Hangcheng Xu, Bin Chen, Ping Yin, Qin Zhou, Jinzhou Huang, Kuntian Luo, Zheming Wu, Huaping Xiao, Xinyi Tu, Jake A. Kloeber, Jiajun Jing, Xiaofeng Huang, Meng Xu Welliver, Zhenkun Lou, Robert Mutter. Cholesterol triggers chromatin stress to drive senescence and inflammation [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 539.