https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/673 2026-04-09T03:04:18Z 2026-04-09T03:04:18Z Lee, Hyo-Jung Cho, Eunho Song, Kwon-Ho Kim, Tae Woo https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/79507 2026-03-17T00:00:12Z 2026-02-01T00:00:00Z

Title: Tumor Cells as Architects of Immune Refractoriness: Dismantling Intrinsic Programs of Tumor Cells for Clinical Translation Authors: Lee, Hyo-Jung; Cho, Eunho; Song, Kwon-Ho; Kim, Tae Woo Abstract: T cell-based immunotherapies have transformed cancer treatment, yet only a minority of patients achieve durable remission because tumors display primary or acquired resistance. While most frameworks attribute therapeutic failure to impaired T-cell activity or immunosuppressive tumor microenvironment (TME), growing evidence indicates that a deeper layer of refractoriness originates within tumor cells themselves. Oncogenic mutations endow tumor cells with survival, and immune-evasive programs, establishing a molecular foundation for multi-malignant and immune-refractory behavior. Under sustained immune pressure and crosstalk with stromal and immune components, these programs are reinforced through epigenetic remodeling and hyperactivation of oncogenic signaling. Importantly, tumor cell-encoded programs extend beyond the cell, orchestrating fibroblast activation, abnormal angiogenesis, suppressed Ag presentation, and recruiting suppressive immune subsets. In this way, tumor cells construct a microenvironment that perpetuates their own resistant state. This review proposes a paradigm shift from an immune-centric to a tumor cell-centric framework, arguing that durable therapeutic control will require dismantling the regulatory networks within tumor cells that couple oncogenesis with immune evasion. By decoding how tumor cells establish and stabilize multilayered immune refractoriness, we outline strategies to identify actionable vulnerabilities and design next-generation therapies that reprogram tumor cells and recondition the TME toward sustained anti-tumor immunity.

2026-02-01T00:00:00Z Son, Sung Wook Lee, Hyo-Jung Kang, Nana Bae, Seongjae Cho, Eunho Kwon, Heeju Yoon, Da-Young Lee, Chaeleen Lee, Seungho Son, Min Kyu Chae, Jisu Kim, Suyeon Oh, Se Jin Sim, Younji Lee, Kyung-Mi Yee, Cassian Woo, Seon Rang Jeong, Yun-Jeong Choi, Hee-Jung Kwak, Jong-Young Lee, Eun-Woo Park, Jinuk Kwak, Sang Gyu Chang, Young-Chae Kim, Tae Woo Song, Kwon-Ho https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/78832 2026-01-26T08:31:43Z 2025-12-01T00:00:00Z

Title: The E2F1-HMGCR axis promotes ferroptosis resistance in immune refractory tumor cells Authors: Son, Sung Wook; Lee, Hyo-Jung; Kang, Nana; Bae, Seongjae; Cho, Eunho; Kwon, Heeju; Yoon, Da-Young; Lee, Chaeleen; Lee, Seungho; Son, Min Kyu; Chae, Jisu; Kim, Suyeon; Oh, Se Jin; Sim, Younji; Lee, Kyung-Mi; Yee, Cassian; Woo, Seon Rang; Jeong, Yun-Jeong; Choi, Hee-Jung; Kwak, Jong-Young; Lee, Eun-Woo; Park, Jinuk; Kwak, Sang Gyu; Chang, Young-Chae; Kim, Tae Woo; Song, Kwon-Ho Abstract: During cancer immunoediting, cancer cells deregulate cell death executioner mechanisms to escape immunotherapy-induced antitumor immunity. Ferroptosis, a type of regulated necrosis triggered by lipid peroxidation, plays a pivotal role in the anti-tumor activity of T cell-based immunotherapies; however, mechanisms for the modulation of ferroptosis in immune-refractory tumor cells are unclear. In this study, using preclinical models of immune refractory tumors obtained following the course of immunoediting by PD-1 blockade and adoptive T cell therapy (ACT), we find that T cell-based immunotherapy drives the development of ferroptosis resistance of tumor cells. In this process, E2F1 is upregulated by immunotherapy and it in turn binds to the promoter of the HMGCR gene to upregulate HMGCR, thereby contributing to the resistance to ferroptosis. Notably, HMGCR inhibition renders immune-refractory tumor cells susceptible to ACT and PD-1 blockade. Thus, our results reveal a mechanism by which cancer cells modulate ferroptosis to acquire resistance to immunotherapy and implicate the E2F1-HMGCR axis as a central molecular target for controlling ferroptosis resistance of immune-refractory cancer.

2025-12-01T00:00:00Z Son, Min Kyu Lee, Hyo-Jung Cho, Eunho Oh, Se Jin Kim, Tae Woo https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/77929 2025-07-24T05:39:26Z 2025-07-01T00:00:00Z

Title: TRPV1 inhibition sensitizes tumors to PD-1 blockade by reversing resistance to CTL-mediated killing Authors: Son, Min Kyu; Lee, Hyo-Jung; Cho, Eunho; Oh, Se Jin; Kim, Tae Woo Abstract: Resistance to immune checkpoint blockade (ICB) therapy remains a major obstacle to successful cancer treatment and represents a significant unmet clinical need. Identifying clinically actionable targets to overcome this resistance is therefore essential for developing effective combination strategies with ICB. In this study, using transcriptomic data from cancer patients treated with programmed cell death protein 1 (PD-1) therapy and established mouse preclinical PD-1 blockade-resistant models, we identify transient receptor potential vanilloid 1 (TRPV1) as a crucial mediator that enables tumor cells to resist cytotoxic T lymphocyte (CTL)-mediated killing, thereby facilitating immune escape from PD-1 therapy. Mechanically, TRPV1 enhances autophagy-dependent secretion of epidermal growth factor (EGF), which in turn activates epidermal growth factor receptor (EGFR) signaling, ultimately leading to tumor cell resistance to CTL-mediated cytotoxicity. Importantly, pharmacological inhibition of TRPV1 sensitizes resistant tumors to PD-1 blockade by restoring anti-tumor immune response. Thus, our findings highlight TRPV1 as a promising therapeutic target for overcoming resistance to PD-1 blockade and provide a strong rationale for combining TRPV1 antagonists with anti-PD-1 therapy. © The Author(s) 2025.

2025-07-01T00:00:00Z Kim, Suyeon Lee, Hyo-Jung Lee, Seungho Chung, Jo Eun Oh, Se Jin Song, Kwon-Ho Cho, Eunho Son, Min Kyu Kwon, Heeju Kim, Seung-Jong Lee, Chaeleen Chang, Suhwan Kim, Tae Woo https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/77673 2025-07-10T03:26:05Z 2025-06-01T00:00:00Z

Title: Cytoplasmic WEE1 Promotes Resistance to PD-1 Blockade Through Hyperactivation of the HSP90A/TCL1/AKT Signaling Axis in NANOG<SUP>high</SUP> Tumors Authors: Kim, Suyeon; Lee, Hyo-Jung; Lee, Seungho; Chung, Jo Eun; Oh, Se Jin; Song, Kwon-Ho; Cho, Eunho; Son, Min Kyu; Kwon, Heeju; Kim, Seung-Jong; Lee, Chaeleen; Chang, Suhwan; Kim, Tae Woo Abstract: Immune checkpoint blockade (ICB) has revolutionized the therapeutic landscape across various cancer types. However, the emergence of resistance to ICB therapy limits its clinical application. Therefore, it is necessary to better understand immune-resistance mechanisms that could be targeted by actionable drugs and important to identify predictive markers for selecting patients. In this study, by analyzing transcriptomic data from patients treated with PD-1 blockade and tumor models refractory to anti-PD-1 therapy, we identified WEE1 as a resistance factor conferring cancer stem cell-like properties as well as immune-refractory phenotypes to tumor cells. WEE1 is transcriptionally upregulated by stemness factor NANOG and predominantly localized in the cytoplasm, not the nucleus, following AKT-dependent S642 phosphorylation in immune-refractory tumor cells. Mechanistically, cytoplasmic WEE1 drove AKT hyperactivation via the HSP90A/TCL1A/AKT auto-amplification loop and upregulated the expression of refractory factors such as CYCLIN A for hyperproliferation and MCL-1 for resistance to T-cell killing. Of note, CXCL10 was downregulated, resulting in insufficient T-cell infiltration. The NANOG/WEE1/AKT axis was also conserved in various human cancers. Importantly, targeting WEE1 with a clinically relevant inhibitor sensitized NANOG+ immune-refractory tumors to ICB, reinvigorating antitumor immunity by disrupting the HSP90A/TCL1A/AKT loop. Thus, our findings demonstrate the oncogenic role of cytoplasmic WEE1 in immune-refractoriness and conferring cancer stem cell-like properties of tumor cells through AKT hyperactivation and provide a rationale for combining a WEE1 inhibitor to control anti-PD-1 therapy-refractory tumors.

2025-06-01T00:00:00Z