Immunotherapy Resistance Research Articles

Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms.

Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms.

Management approaches for recurrent or metastatic head and neck squamous cell carcinoma after anti-PD-1/PD-L1 immunotherapy.

Management approaches for recurrent or metastatic head and neck squamous cell carcinoma after anti-PD-1/PD-L1 immunotherapy.

FMO2+ cancer-associated fibroblasts sensitize anti-PD-1 therapy in patients with hepatocellular carcinoma.

The efficacy of immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) is limited by heterogeneity in individual responses to therapy. The heterogeneous phenotypes and crucial roles of cancer-associated fibroblasts (CAFs) in immunotherapy resistance remain largely unclear. A specific CAF subset was identified by integrating comprehensive single-cell RNA sequencing, spatial transcriptomics and transcriptome profiling of patients with HCC with different responses to antiprogrammed cell death protein 1 (anti-PD-1) therapy. Mouse orthotopic HCC models and a coculture system were constructed, and cytometry by time-of-flight analysis was performed to investigate the functions and mechanisms of specific CAFs in the immune context of HCC. We identified a distinct flavin-containing monooxygenase 2 (FMO2)+ CAF subset associated with a favorable response to anti-PD-1 therapy and better clinical outcomes. FMO2+ CAFs increase anti-PD-1 treatment efficacy by promoting tertiary lymphoid structure formation and increasing the infiltration of CD8+ T cells and M1-like macrophages through the C-C motif chemokine ligand 19 (CCL19)-C-C motif chemokine receptor 7 axis. Mechanistically, FMO2 promotes nuclear factor kappa B/p65-mediated CCL19 expression by competitively binding to glycogen synthase 1 (GYS1) with praja ring finger ubiquitin ligase 1 (PJA1), thereby suppressing the PJA1-mediated proteasomal degradation of GYS1. CCL19 treatment potentiated the therapeutic efficacy of anti-PD-1 therapy in mouse orthotopic HCC models. A favorable immunotherapy response was observed in patients with HCC with high serum levels of CCL19. We identified a novel FMO2+ CAF subset that serves as a critical regulator of microenvironmental immune properties and a predictive biomarker of the immunotherapy response in patients with HCC. CCL19 in combination with anti-PD-1 therapy may constitute a novel therapeutic strategy for HCC.

Circular RNA CDYL facilitates hepatocellular carcinoma stemness and PD-L1+ exosomes-mediated immunotherapy resistance via stabilizing hornerin protein by blocking synoviolin 1-mediated ubiquitination.

Circular RNA CDYL facilitates hepatocellular carcinoma stemness and PD-L1+ exosomes-mediated immunotherapy resistance via stabilizing hornerin protein by blocking synoviolin 1-mediated ubiquitination.

Deep scSTAR: leveraging deep learning for the extraction and enhancement of phenotype-associated features from single-cell RNA sequencing and spatial transcriptomics data.

Single-cell sequencing has advanced our understanding of cellular heterogeneity and disease pathology, offering insights into cellular behavior and immune mechanisms. However, extracting meaningful phenotype-related features is challenging due to noise, batch effects, and irrelevant biological signals. To address this, we introduce Deep scSTAR (DscSTAR), a deep learning-based tool designed to enhance phenotype-associated features. DscSTAR identified HSP+ FKBP4+ T cells in CD8+ T cells, which linked to immune dysfunction and resistance to immune checkpoint blockade in non-small cell lung cancer. It has also enhanced spatial transcriptomics analysis of renal cell carcinoma, revealing interactions between cancer cells, CD8+ T cells, and tumor-associated macrophages that may promote immune suppression and affect outcomes. In hepatocellular carcinoma, it highlighted the role of S100A12+ neutrophils and cancer-associated fibroblasts in forming tumor immune barriers and potentially contributing to immunotherapy resistance. These findings demonstrate DscSTAR's capacity to model and extract phenotype-specific information, advancing our understanding of disease mechanisms and therapy resistance.

Comprehensive characterization of T cell subtypes in lung adenocarcinoma: Prognostic, predictive, and therapeutic implications.

Comprehensive characterization of T cell subtypes in lung adenocarcinoma: Prognostic, predictive, and therapeutic implications.

Re: Aram Lyu, Zenghua Fan, Matthew Clark, et al. Evolution of Myeloid-mediated Immunotherapy Resistance in Prostate Cancer. Nature 2025;637:1207–17

Re: Aram Lyu, Zenghua Fan, Matthew Clark, et al. Evolution of Myeloid-mediated Immunotherapy Resistance in Prostate Cancer. Nature 2025;637:1207–17

CXCL6 Reshapes Lipid Metabolism and Induces Neutrophil Extracellular Trap Formation in Cholangiocarcinoma Progression and Immunotherapy Resistance.

The chemokine CXCL6 is identified as a pivotal regulator of biological processes across multiple malignancies. However, its function in cholangiocarcinoma (CCA) is underexplored. Tumor profiling for CXCL6 is performed using a public database. Both in vitro and in vivo experiments are utilized to evaluate the oncogenic effects of CXCL6 on CCA. Additionally, RNA-Seq is employed to detect transcriptomic changes related to CXCL6 expression in CCA cells and neutrophils. Molecular docking, fluorescence colocalization, and Co-IP are used to elucidate a direct interaction between JAKs and CXCR1/2. Additionally, LC-MS lipidomics and explored the impact of CXCL6 on immunotherapy in vivo. CXCL6 is upregulated in CCA tissues and promoted the proliferation and metastasis of CCA. Mechanistically, CXCL6 regulated the CXCR1/2-JAK-STAT/PI3K axis in CCA via autocrine signaling, leading to lipid metabolic reprogramming, and promoted neutrophil extracellular traps (NETs) formation by activating the RAS/MAPK pathway in neutrophils. Eventually, NETs formation induced immunotherapy resistance in CCA by blocking CD8+T cell infiltration. CXCL6 modulates CCA progression through the CXCR1/2-JAK-STAT/PI3K axis and reshaping its lipid metabolism. CXCL6 also mediates immunotherapy resistance through NETs, which may be a potential therapeutic target and biomarker for CCA.

Inflammation, Immunosuppression, and Immunotherapy in Pancreatic Cancer-Where Are We Now?

Pancreatic cancer (PC) is one of the most commonly diagnosed and deadliest neoplasms in the modern world. Over the past few years, the incidence of PC has risen with only a slight improvement in overall survival. Moreover, the improvement in survival is primarily driven by diagnoses in the localized stage of the disease, rather than by new treatment methods. The inflammatory process is a key mediator of PC development, yet PC is also one of the most immune-resistant tumors. Patients rarely benefit from monotherapy with immune checkpoint inhibitors; nevertheless, the latest biological findings on the complexity of the pancreatic tumor microenvironment might be translated into designing new clinical studies that combine various approaches to overcome single-agent immunotherapy resistance. On the other hand, focusing on inflammation may lead to the development of new inflammation-based prognostic markers for patients. This review aims to describe the current state of knowledge regarding the complex relationships between systemic and local inflammation, immune response, immunosuppression, and therapeutic options in PC.

FOXM1 could serve as a bridge mediating prognosis and immunity for clear cell renal cell carcinoma via single-cell and bulk RNA-sequencing

BackgroundIn the development of several cancers, the Forkhead Box M1 (FOXM1) is crucial. The relationship between the immune system and FOXM1 in renal cell carcinoma (ccRCC), which has been verified by bulk RNA sequencing and scRNA sequencing, is the primary subject of this research.MethodPublicly available data related to FOXM1 and ccRCC were extracted from The Cancer Genome Atlas (TCGA) database. The impact of FOXM1 on the prognosis of ccRCC was examined using Cox regression analysis. Results were verified by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Additionally, single-cell sequencing data were analyzed.ResultsWhen compared to para-carcinoma tissues, the expression of FOXM1 was considerably higher in ccRCC tissues. Patients with elevated FOXM1 expression had lower survival rates. FOXM1 may be a standalone prognostic factor for ccRCC, according to results of univariate and multivariate Cox regression studies. Reduced FOXM1 expression was linked to higher immunotherapy sensitivity, according to immunocorrelation analysis. This suggests FOXM1 may mediate immunotherapy resistance in ccRCC. Additionally, FOXM1 showed strong associations with tumor mutation load, microsatellite instability, and antitumor immunity. These results imply FOXM1 may regulate antitumor immunity in the ccRCC microenvironment. Consistent results from immunohistochemistry, PCR, and single-cell RNA sequencing confirmed upregulated FOXM1 expression in ccRCC.ConclusionsAccording to the findings, FOXM1 might be used as a stand-alone prognostic biomarker for ccRCC. Moreover, FOXM1 has exhibited robust correlations with microsatellite instability, tumor mutation burden, immune response, and immunotherapy efficacy. FOXM1 may promote ccRCC pathogenesis partly by suppressing antitumor immunity and mediating immunotherapy resistance.

Crosstalk between the tumor immune microenvironment and metabolic reprogramming in pancreatic cancer: new frontiers in immunotherapy.

In recent years, the incidence and mortality of pancreatic cancer (PC) are increasing year by year. The highly heterogeneous nature of PC, its strong immune escape ability and easy metastasis make it the most lethal malignant tumor in the world. With the rapid development of sequencing technology, the complex components in the tumor microenvironment (TME) of PC have been gradually revealed. Interactions between pancreatic stellate cells, tumor-associated fibroblasts, various types of immune cells, and cancer cells collectively promote metabolic reprogramming of all types of cells. This metabolic reprogramming further enhances the immune escape mechanism of tumor cells and ultimately induces tumor cells to become severely resistant to chemotherapy and immunotherapy. On the one hand, PC cells achieve re and rational utilization of glucose, amino acids and lipids through metabolic reprogramming, which in turn accomplishes biosynthesis and energy metabolism requirements. Under such conditions, tumorigenesis, proliferation and metastasis are ultimately promoted. On the other hand, various types of immune cells in the tumor immune microenvironment (TIME) also undergo metabolic reprogramming, which leads to tumor progression and suppression of anti-immune responses by inhibiting the function of normal anti-tumor immune cells and enhancing the function of immunosuppressive cells. The aim of this review is to explore the interaction between the immune microenvironment and metabolic reprogramming in PC. The focus is to summarize the specific mechanisms of action of metabolic reprogramming of PC cells and metabolic reprogramming of immune cells. In addition, this review will summarize the mechanisms of immunotherapy resistance in PC cells. In the future, targeting specific mechanisms of metabolic reprogramming will provide a solid theoretical basis for the development of combination therapies for PC.

Targeting the Senescent Tumor Microenvironment to Sensitize Immunotherapy

The tumor microenvironment (TME) plays a pivotal role in cancer progression, metastasis, and therapeutic resistance. Cellular senescence within the TME, characterized by irreversible growth arrest and the senescence-associated secretory phenotype (SASP), profoundly impacts tumor biology and immunotherapy efficacy. The senescent TME promotes tumor growth, invasion, and metastasis through complex interactions between senescent cells, SASP factors, and the extracellular matrix (ECM). Simultaneously, senescence-induced alterations in immune cell function, including T cell exhaustion, macrophage polarization, and impaired natural killer (NK) cell cytotoxicity, contribute to an immunosuppressive niche that hinders immunosurveillance and fosters tumor immune evasion. Mounting evidence suggests that the senescent TME is a critical mediator of resistance to immune checkpoint inhibitors (ICIs). Senescence-associated changes in the TME dampen antitumor immunity by reducing CD8+ T cell infiltration and functionality while promoting the accumulation of immunosuppressive cell populations such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Consequently, strategies targeting the senescent TME have emerged as promising approaches to enhance ICI efficacy. Senolytic agents, SASP inhibitors, and combinatorial therapies aimed at eliminating senescent cells, modulating SASP, and reprogramming the immunosuppressive TME have shown potential in preclinical models to sensitize tumors to immunotherapy. As our understanding of the senescent TME evolves, it is becoming increasingly clear that a multifaceted approach integrating TME-targeted interventions with immunotherapy is necessary to overcome resistance and improve patient outcomes. Future research should focus on elucidating the molecular mechanisms underlying senescence-driven immunotherapy resistance, identifying robust biomarkers to predict treatment response, and developing novel therapeutic strategies that synergize with ICIs. By harnessing the potential of TME-targeted approaches, we can expand the scope and efficacy of cancer immunotherapy, ultimately leading to improved survival and quality of life for cancer patients.

The Efficacy of Targeted Monoclonal IgA Antibodies Against Pancreatic Ductal Adenocarcinoma.

The efficacy of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) remains limited. The tumor microenvironment (TME), characterized by the accumulation of suppressive myeloid cells including neutrophils, attributes to immunotherapy resistance in PDAC. IgA monoclonal antibodies (mAbs) can activate neutrophils to kill tumor cells; this can be further enhanced by blocking the myeloid immune checkpoint CD47. In this study, we investigated the potential of this therapeutic strategy for PDAC. We determined the expression of tumor-associated antigens (TAAs) on PDAC cell lines and fresh patient samples, and the results showed that the TAAs epithelial cell adhesion molecule (EpCAM), trophoblast cell surface antigen 2 (TROP2) and mucin-1 (MUC1), as well as CD47 were consistently expressed on PDAC. In line with this, we showed that IgA mAbs against EpCAM can activate neutrophils to lyse various PDAC cell lines and tumor cells, which can be augmented by addition of CD47 blockade. In addition, we observed that neutrophils were present in patient tumors and expressed the receptor for IgA. In conclusion, our results indicate that a combination of IgA mAb with CD47 blockade is a promising preclinical treatment strategy for PDAC, which merits further investigation.

CDKN2Alow tumours mediate immunotherapy resistance by depriving macrophages of zinc.

CDKN2Alow tumours mediate immunotherapy resistance by depriving macrophages of zinc.

Abstract 3279: Smoking burden is associated with immunotherapy resistance in extensive stage small cell lung cancer

Abstract Small cell lung cancer (SCLC) remains the deadliest histologic lung cancer subtype with a median survival of only ∼12 months among patients with extensive stage (ES) disease. SCLC is strongly associated with heavy tobacco use, yet the effect of tobacco use on therapeutic outcomes remains understudied. Recent data from our group showed that the subtype of SCLC with inflammatory gene signatures (SCLC-I) responds better to immunotherapy (IO) than the other subtypes. Given the association between smoking and inflammation, we hypothesized that heavy smoking may correlate with better IO responses and enrichment in the SCLC-I subtype. To investigate this, we evaluate the outcomes of ES-SCLC patients treated at MD Anderson between 2017-2024 (N=521) and compared those who received chemotherapy plus IO (N=263) to those who received chemo alone (N=258). Transcriptional changes were evaluated across different tobacco pack-year cohorts using the GEMINI bulk RNAseq database of MD Anderson SCLC tumors (N=81). The median overall survival (mOS) for all ES-SCLC patients was 13.3 months. Immunotherapy provided an added 1-month benefit in mOS over chemotherapy alone, extending mOS from 12.1 to 13.1-months (HR=0.88; p=0.21); consistent with historic cohorts. Patients were then stratified by the cohort pack-year median of 40. For patients with ≤ 40 pack-year smoking histories, the addition of IO improved mOS by 3.7-months from 11.5 to 14.3-months (HR=0.74; p=0.03). However, those with >40 pack-year smoking histories demonstrated no benefit from added IO (13.0 to 12.2-months (HR=1.06; p=0.70). Further analysis by pack-year tertiles (0-24, 25-49, 50+) showed mOS benefits of 5.4 months (HR: 0.67, P=0.05), 1.6m (HR:0.91, P=0.62), and 0.7m (HR=1.01, P=0.679) respectively, for chemo plus IO vs chemo alone. Despite better IO outcomes among patients with 0-40 pack-years, the SCLC-I subtype was underrepresented in the 0-40 pack-year group compared to expectation using the GEMINI RNAseq database (chi-squared 8.2; p=0.04). Tobacco exposure positively correlated with absolute immune cell infiltration by CIBERSORTx (R=0.24; p=0.03), although driven by higher immunosuppressive T cell signatures. Tumors from the 50+ pack-year (upper smoking tertile) group also demonstrated elevated chronic inflammatory GSEA signatures and genes associated with microenvironment immune suppression compared to the 0-24 (lower smoking tertile) pack-year group. The discovery that smoking is linked to immunotherapy resistance in SCLC represents a novel contribution to our understanding of the disease and its treatment. By identifying immunosuppressive cellular infiltrates and immunosuppressive gene signatures among patients with heavy vs light smoking histories, we have identified potentially targetable mechanisms of immune evasion. This represents a new lens through which to study immunotherapy resistance in SCLC. Citation Format: Kyle Concannon, Benjamin Morris, Lixia Diao, Moushumi Sahu, Whitney Lewis, Xiaowen Sun, Simon Heeke, Bingnan Zhang, Hai Tran, Lingzhi Hong, Waree Rinsurongkawong, Minh Nguyen, Kang Qin, Hui Li, Jainjun Zhang, Jack Lee, Jing Wang, Robert Cardnell, Carl Gay, John Heymach, Lauren Byers. Smoking burden is associated with immunotherapy resistance in extensive stage small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3279.

Abstract 635: Unraveling the potential of neogenin 1 in non-small cell lung cancer: A path toward innovative combination therapies

Non-small cell lung cancer (NSCLC) has a poor survival rate due to delayed diagnosis and treatment resistance. Currently, immunotherapy has advanced the NSCLC treatment; however, only a small fraction of patients respond to the therapy, demanding the identification of novel biomarkers associated with resistance to develop new therapeutic strategies. Herein, we investigated the role of neogenin 1, a transmembrane protein that belongs to the immunoglobulin superfamily, in seven different human NSCLC cell lines and compared the expression with Jurkat T cell line and human peripheral blood mononuclear cell (PBMC)-derived CD3/CD28-activated CD8+ T cells using qPCR and western blot. We also performed the cell proliferation assay in adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) human cell lines after knockdown and overexpression of neogenin 1. We found that neogenin 1 was highly expressed in primary CD8+ T cells compared to the cancer cell lines, implying that genetic alteration of neogenin 1 might interfere more with CD8+ T cell effector function. We also discovered that both adenocarcinoma and squamous cell carcinoma cell proliferation ability were influenced by genetic alteration of neogenin 1. In addition, gene ontology enrichment analysis and KEGG pathway analysis indicated that neogenin 1 was involved in the TGF-beta signaling pathway, possibly suggesting that neogenin 1 might play a role in therapeutic resistance, including immunotherapy, in NSCLC. Correlation analysis in LUAD and LUSC in the TCGA dataset also revealed that neogenin 1 was positively correlated with a set of genes, such as IGF1R and USP8, associated with immunotherapy resistance. Further investigation of this potential gene in vivo will unfold its role in immunotherapy resistance in NSCLC, paving the way for developing novel and effective combinatorial therapeutic strategies targeting neogenin 1. Citation Format: Asmita Pandey, Shaoqiu Chen, Li Ma, Mayumi Jijiwa, Masaki Nasu, Vedbar Khadka, Yu Chen, Hua Yang, Sudhir Rai, Youping Deng. Unraveling the potential of neogenin 1 in non-small cell lung cancer: A path toward innovative combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 635.

Abstract 113: Decoding developmental programs driving tumorigenesis and immunotherapy resistance in triple-negative breast cancer

Abstract 113: Decoding developmental programs driving tumorigenesis and immunotherapy resistance in triple-negative breast cancer

Abstract 916: Tumor extracellular vesicles trigger a dendritic cell stress response to promote immune evasion and immunotherapy resistance

Abstract 916: Tumor extracellular vesicles trigger a dendritic cell stress response to promote immune evasion and immunotherapy resistance

Abstract 3819: Modeling T cell and cancer cell interactions to examine immune checkpoint inhibition resistance in pancreatic cancer

Abstract Pancreatic cancer (PC) is a lethal cancer, with ∼90% of patients dying within 5 years. This dire statistic underscores the limitations of current treatments and the need for improved therapeutic approaches. Immune checkpoint inhibition (ICI) has shown promise in promoting long-term progression-free survival across various cancers by reactivating a patients’ latent anti-cancer immune response. However, PC is almost completely resistant to ICI, highlighting the incomplete understanding of immune-cancer interactions in this disease. The tumor microenvironment is a key factor in immunotherapy resistance in PC, where immunosuppressive immune cells and cancer-associated fibroblasts (CAFs) act to inhibit T cell function. Additionally, the extracellular matrix (ECM) landscape of PC presents a physical barrier to T cell infiltration and motility within the tumor. Developing strategies to overcome these barriers has been challenging, partly due to the difficulty in replicating the complex PC tumor microenvironment in experimental models. The use of 3D cancer tumoroid cultures enables modeling of cancer and stromal cells spatial arrangements, mimicking native tumor microenvironments and facilitating high resolution examination of cell-to-cell and cell-to-environment interactions. However, most tumoroid cultures often use commercial matrix products like basement membrane extracts (BME), which poorly recapitulate the distinct biochemical and mechanical properties inherent to PC tumors. Here, we utilize the Inventia RASTRUMTM platform to create 3D cancer/CAF/T cell co-cultures based on synthetic PEG-based hydrogel matrices, which were tuned to mimic the stiffness and ECM composition of PC tumors. Using real-time longitudinal imaging and 3D image analysis pipelines, we visualize cancer-stromal cell interactions, which are obscured in conventional BME-based models. We also investigate the role of CAFs in supporting immune evasion and highlight the effect of multiple immunomodulators on cancer/T cell behavioral dynamics. Overall, our approach provides a scalable in vitro framework to dissect cell-to-cell interactions and offers a platform to the profile immunomodulatory properties of drugs. Future work using this platform will focus on molecular profiling of cancer-CAF-T cell interactions to provide predictive data aiding the rational design and evaluation of ICI combination therapies prior to pre-clinical in vivo work and clinical translation. Citation Format: Aji Istadi, Inna Navarro, Silvia Lombardi, Dannielle Upton, Mezzalina Vankan, Cesar Moreno, Michael Trpceski, Cecilia Chambers, David Hermann, Marco Herold, Paul Timpson, Sean Porazinski, Greg Neely, Marina Pajic. Modeling T cell and cancer cell interactions to examine immune checkpoint inhibition resistance in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3819.

Abstract 5296: Hepatocellular carcinoma resistance and recurrence to anti-PD-1 therapy is associated with tumor heterogeneity and plasticity driven by MYC

Abstract Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and a major cause of cancer-related deaths worldwide. HCC is characterized by low survival rates and a high incidence of recurrence. Systemic therapy responses are observed in only a small proportion of HCC patients. Our spatial transcriptomics (ST) analysis of HCC tumors from patients treated with anti-PD-1 and cabozantinib (a multi-tyrosine kinase inhibitor) suggested that immunotherapy resistance is driven by cancer cell heterogeneity, tumor microenvironment (TME) dynamics, and cancer cell plasticity. These mechanisms were detected in an HCC sample collected from a responder who later experienced recurrence. To understand the genomic drivers of resistance and recurrence in HCC, we performed new bioinformatic analyses to investigate the molecular mechanisms associated with HCC plasticity that result in anti-PD-1 resistance. Across our ST samples, we observed up-regulation of oncogenic and immune evasion mechanisms following anti-PD-1 treatment. Interestingly, these signaling pathways share a common upstream modulation by MYC. Gene set enrichment analysis identified a significant upregulation of the MYC pathway in immune-poor cancer regions. Spatially weighted correlation analysis revealed that MYC upregulation is colocalized with cancer cell-intrinsic pathways, such as proliferation, metabolism, and cell plasticity, and is spatially exclusive with immune-related pathways, including antigen presentation and interferon-gamma response. Moreover, intercellular interaction analysis showed that MYC-upregulated cancer cells engage in crosstalk with cancer-associated fibroblasts (CAFs) via PDGF-PDGFR signaling, which is associated with the epithelial-mesenchymal transition (EMT) process, a hallmark of cell plasticity. Our findings were validated in additional anti-PD-1-treated HCC single-cell and ST public datasets, confirming that therapy-reinvigorated lymphocytes neutralize only MYC-downregulated HCC cells, leaving MYC-high HCC cells to survive. These residual HCC cells potentially become the source of tumor recurrence. Our findings highlight MYC as a key regulator of therapeutic resistance and immune suppression in HCC, potentially serving as a target for future interventions to delay anti-PD-1 treatment relapse and improve patient outcomes. Citation Format: Shuming Zhang, Ludmila Danilova, Jacob T. Mitchell, Iris Kwon, Aleksander S. Popel, Mark Yarchoan, Elizabeth M. Jaffee, Elana J. Fertig, Luciane T. Kagohara. Hepatocellular carcinoma resistance and recurrence to anti-PD-1 therapy is associated with tumor heterogeneity and plasticity driven by MYC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5296.