Abstract Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but resistance limits its clinical effectiveness. Therefore, understanding immune resistance mechanisms and identifying predictive markers are essential. Our transcriptomic analysis of PD-1 blockade-treated patients and non-responsive tumor models identifies WEE1 as a key resistance factor, promoting cancer stem cell (CSC)-like traits and immune resistance phenotypes including low T cell infiltrated into tumor and anti-apoptotic properties to cytotoxic T cells (CTLs). WEE1 drives AKT hyperactivation, enhancing expression of resistance factors such as CYCLIN A which contributes to CSC-like properties, and the anti-apoptotic molecule MCL-1, while also reducing T cell infiltration via CXCL10 downregulation. This signaling axis is conserved across various cancers. Notably, WEE1 inhibition sensitizes tumors to ICB by disrupting these refractory properties and reinvigorating antitumor immunity. These findings underscore the novel role of WEE1 in driving immune resistance and CSC-like characteristics, supporting the use of WEE1 inhibitors as a strategy to overcome resistance to anti-PD-1 therapy. Citation Format: Hyo-Jung Lee, Suyeon Kim, Eunho Cho, Tae Woo Kim. WEE1 confers resistance to PD-1 blockade via hyperactivation of the AKT signaling pathway [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B036.

Abstract Cancer immunotherapy, particularly T cell-mediated therapy such as immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT), has emerged as a potentially powerful approach to cancer treatment. However, immunotherapeutic resistance limits its clinical success by disrupting one or more steps of the cancer immunity cycle. In addition, multi-malignant phenotypes of immune-refractory tumor cells are also one of the major causes result poor prognosis of patients. Therefore, identifying the immune-resistance and multi-malignant factor, which not only can be targeted by clinically available medicines it can also be a prognostic marker, is needed ideally. Here, we identified TCTP as a novel factor conferring multi-malignant phenotypes of immune-refractory tumor cells. We discovered a crucial role of TCTP at the crossroads between multi-malignant tumor cells and the anti-cancer immunity system by demonstrating that TCTPhigh tumor cells enriched by immune selection pressure drive immune-refractory phenotypes. Importantly, the levels of TCTP within the tumors significantly correlated with the clinical outcome of anti-PD-L1 therapy, which demonstrate TCTP as a prognostic marker in the case of clinical trials. Furthermore, targeting TCTP by clinical available drug enhanced the response to T cell-mediated therapy including ICB and ACT. Thus, our findings emphasize that TCTP could be a both a valid target a prognostic marker providing a framework for patient selection to apply combined therapy of T cell-mediated therapy with TCTP-targeting agents. Citation Format: Hyo-Jung Lee, Tae Woo Kim. Targeting TCTP reverses the multi-malignant phenotypes of immune-refractory tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6440.