Spatiotemporally programmed nanomedicine engineering to resolve conflicting immunosignals in triple-negative breast cancer

Signal Transduction and Targeted Therapy ARTICLE www.nature.com/sigtrans OPEN Spatiotemporally programmed nanomedicine engineering to resolve conflicting immunosignals in triple-negative breast cancer 1234567890();,: Xiuping Guo1, Wensheng Zheng2, Kaichao Song1, Tingting Zhang1, Zhigang Luo2, Zhouguang Hui3, Qingbo Chen1, Yuting Qin4, Yanan Sun1, Chujuan Hu1, Xiaolian Tian1, Sitong Yang1, Ling Ren1, Quanyong Yu5, Haoyang Yu1, Bozhao Li4, Yingying He1, Yuanbin Li1, Mingyu Pan6, Yongsheng Che1 ✉, Guangjun Nie 4 ✉, Jiandong Jiang 1,2 ✉ and Lulu Wang1 ✉ In triple-negative breast cancer (TNBC), chemotherapy-induced immunogenic cell death (ICD) often fails to trigger truly effective antitumor immunity. This failure primarily stems from the simultaneous release of damage-associated molecular patterns (DAMPs) and immunosuppressive prostaglandin E2 (PGE2), creating an intrinsic NOT-AND signaling conflict. This barrier hinders efficient immune priming, a response rarely induced by conventional chemotherapy. To address this conflict while minimizing toxicity, RGem@Cel-PV, a spatiotemporally programmed nanovesicle, was designed to impose both spatial localization and sequential signal control within the tumor microenvironment. Following preferential accumulation in tumor tissue, enzymatic disassembly of the nanomedicine triggers the rapid release of celecoxib to suppress local PGE2 signaling and alleviate immune suppression. Subsequently, the delayed activation of a phospholipid-gemcitabine prodrug induces DAMP-releasing cell death. This temporal decoupling—unachievable with free drug combinations—converts gemcitabine from a weak ICD inducer into a potent one. In TNBC models, R-Gem@Cel-PV boosted dendritic cell maturation, orchestrated a robust antitumor immune response, and significantly inhibited both primary tumor growth and metastasis. These findings demonstrate that resolving the immunosignal conflict through precise spatiotemporal control is essential for effective immune engagement in TNBC and offer a generalizable strategy for reprogramming the immune response to chemotherapy in immune-refractory tumors. Signal Transduction and Targeted Therapy (2026)11:215 INTRODUCTION Traditional anticancer therapies have long viewed tumor cell death as the primary biological and therapeutic endpoint, with chemotherapy serving as a cornerstone for treating unresectable malignancies1,2. While the direct tumoricidal effects of chemotherapeutic agents are well established, the resulting cell death triggers a cascade of events that profoundly reshape the tumor microenvironment (TME), ultimately influencing therapeutic outcomes. One potential immunological benefit of chemotherapy is the induction of immunogenic cell death (ICD)3–5, a regulated form of cell death characterized by the release of damage-associated molecular patterns (DAMPs)6–8. These signals promote dendritic cell (DC) maturation and antigen presentation, linking cytotoxic therapy to adaptive antitumor immunity. However, in many solid tumors, this pro-immunogenic potential is rarely realized6,9. A major contributing factor is the concurrent induction of cyclooxygenase-2 (COX2) expression and subsequent production ; https://doi.org/10.1038/s41392-026-02685-6 of prostaglandin E2 (PGE2) by several chemotherapeutic agents9,10. PGE2 is a potent immunosuppressive mediator that impairs DC function11, inhibits T-cell activity12,13, and has been proposed to act as an inhibitory DAMP (iDAMP), counteracting ICD-associated immune activation14. Thus, combining chemotherapy with COX2 or PGE2 inhibition has been explored as a strategy to resolve this signaling conflict. However, such combinations have shown limited and inconsistent benefits in both preclinical and clinical studies15–17. The reasons for this failure remain incompletely understood, representing a critical barrier to the rational design of chemoimmunotherapeutic strategies. Notably, most combination approaches have focused on the presence or absence of immunosuppressive signaling while largely neglecting the temporal coordination between immune suppression relief and ICD induction. Emerging evidence highlights that the temporal sequence of combination therapies is a key determinant of their immunomodulatory outcomes and overall efficacy18,19. For example, the 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Key Technologies and Application for Research and Development of New Anti-infective Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; 2Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; 3Department of VIP Medical Services, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; 4CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center of Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China; 5China Pharmaceutical University, Nanjing, China and 6University of California-Riverside, Riverside, CA, USA Correspondence: Yongsheng Che () or Guangjun Nie () or Jiandong Jiang () or Lulu Wang () These authors contributed equally: Xiuping Guo, Wensheng Zheng, Kaichao Song, Tingting Zhang, Zhigang Luo Received: 31 May 2025 Revised: 2 February 2026 Accepted: 12 March 2026 © The Author(s) 2026 Spatiotemporally programmed nanomedicine engineering to resolve. . . Guo et al. 2 CheckMate 064 study in melanoma demonstrated that initiating treatment with nivolumab followed by ipilimumab resulted in superior outcomes, whereas the reverse sequence induced immunosuppressive T-cell phenotypes, leading to resistance to subsequent nivolumab20,21. Consequently, the efficacy of immunotherapy may be influenced by the preexisting immunological landscape22. In the TME, elevated PGE2 fosters an immunosuppressive state, which is further amplified by chemotherapyinduced PGE2 signaling, impairing the immune system’s response to chemotherapy-induced DAMPs. In such a TME, dominated by immunosuppressive mediators such as PGE2, ICD-associated signals may be functionally silenced, rendering the cytotoxic event immunologically ineffective23–25. These findings support a fundamental immunological premise: the immunogenic potential of chemotherapy-induced ICD depends on a permissive TME in which PGE2-mediated immunosuppression has been alleviated. This issue is particularly pronounced in triple-negative breast cancer (TNBC), an aggressive subtype where cytotoxic chemotherapy remains the primary treatment modality26,27. The TME of TNBC is heavily reliant on PGE2 signaling, contributing to severe immune suppression and resistance to immunotherapy28,29. The disappointing outcomes of combining chemotherapy with celecoxib in TNBC models illustrate the l (...truncated)