Theranostics - Targeting CAMK1D-engineered nanoactivator suppresses cancer stem cell maintenance and immune evasion in enzalutamide-resistant prostate cancer - Research Paper

Sep 30, 2026

Hormonal therapy is essential for prostate cancer management, yet long-term efficacy is limited by enzalutamide resistance driven by prostate cancer stem-like cells and an immunosuppressive tumor microenvironment. A CD44-targeted nanoactivator (EC@HNA) was engineered to co-deliver enzalutamide and siCAMK1D, enabling characterization of physicochemical behavior, uptake, and gene-silencing. Mechanistic studies evaluated stemness programs and immune modulation via cytokine control, Treg infiltration, macrophage polarization, and CREB-dependent regulation. In resistant models including cell cultures, murine tumors, and patient-derived organoids, EC@HNA suppressed CAMK1D, reduced IL-10/TGF-β, promoted M1-like macrophages, enhanced CD8+ cytotoxicity, diminished stemness regulators, and restored anti-tumor immunity with minimal systemic toxicity.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Abstract

Rationale

Methods

Results

Conclusions

Introduction

Theranostics 2026, Vol. 16, Issue 6 2918 Ivyspring International Publisher Theranostics 2026; 16(6): 2918-2935. doi: 10.7150/thno.120826 Research Paper Targeting CAMK1D-engineered nanoactivator suppresses cancer stem cell maintenance and immune evasion in enzalutamide-resistant prostate cancer Feifei Sun1, 3*, Yuchuan Yan1*, Deqing Sun2*, Shijia Liu1, Zhaoru Dong1, Guoqiang Pan1, Lin Zhang4, Xianhao Shao5, Yuliang Xu2, Ying Qu2􀀍, Tao Li1􀀍 1. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China. 2. Department of Pharmacy, The Second Qilu Hospital of Shandong University, Jinan, 250033, China. 3. Department of Pathology, Peking University People's Hospital, Beijing, China. 4. Binzhou Center for Disease Control and Prevention, Binzhou, Shandong, China. 5. Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China. *These authors contributed equally: Feifei Sun, Yuchuan Yan, and Deqing Sun. 􀀍 Corresponding authors: Ying Qu M.D., Department of Pharmacy, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China; [E-mail: yingqu@email.sdu.edu.cn. Tao Li M.D](E-mail: yingqu@email.sdu.edu.cn. Tao Li M.D)., Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, China; E-mail: [litao7706@163.com](litao7706@163.com). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.07.02; Accepted: 2025.11.27; Published: 2026.01.01 Abstract Rationale: Hormonal therapy is fundamental to prostate cancer (PCa) management; however, its long-term efficacy is compromised by enzalutamide resistance (ENZR), which is fuelled by prostate cancer stem-like cells (PCaSCs) and an immunosuppressive microenvironment. Methods: A CD44-targeted nanoactivator (EC@HNA) was engineered to co-deliver ENZ and siCAMK1D. Its physicochemical properties, cellular uptake and gene-silencing efficiency were characterized in vitro. Functional and mechanistic assays were used to assess PCaSCs expansion, cytokine modulation, immune cell dynamics, and CREB-dependent regulation of stemness genes. Therapeutic efficacy and safety were validated in ENZR cell cultures, murine tumor models, and patient-derived organoids. Results: EC@HNA efficiently delivered siCAMK1D and achieved potent CAMK1D silencing, thereby significantly suppressing the expansion and self-renewal of PCaSCs. This treatment downregulated the immunosuppressive cytokines IL-10 and TGF-β, decreased regulatory T cell (Treg) infiltration, promoted M1-like polarization of tumor-associated macrophages, and enhanced CD8⁺ T cell infiltration and cytotoxicity in ENZR prostate tumors, thereby reprogramming the tumor immune microenvironment. Mechanistically, EC@HNA suppressed CREB phosphorylation at Ser133, which transcriptionally repressed key stemness regulators, including CD44, CD133, and NR4A1, thereby attenuating tumor stemness and immune evasion. These effects have been validated using in vitro cell models, ENZR xenografts, and patient-derived organoids. Collectively, EC@HNA dismantled the stemness-immunity axis sustaining ENZR and restored robust anti-tumor immunity with minimal systemic toxicity. Conclusions: Overall, the CD44-targeted EC@HNA nanoplatform disrupted stemness programs and restored tumor-immune surveillance, representing a promising strategy to reverse ENZR and potentiate immunotherapy in clinical ENZR PCa patients. Keywords: enzalutamide-resistant prostate cancer; CAMK1D; engineered lipid-based nanoactivator; stemness; immune evasion Introduction Prostate cancer (PCa) remains a leading cause of can

FAQs

What problem does the study address in enzalutamide-resistant prostate cancer?

The study targets enzalutamide resistance caused by prostate cancer stem-like cells and an immunosuppressive tumor microenvironment.

What is EC@HNA and what does it deliver?

EC@HNA is a CD44-targeted nanoactivator engineered to co-deliver enzalutamide and siCAMK1D for gene silencing of CAMK1D.

How does EC@HNA affect both cancer stemness and tumor immunity?

EC@HNA suppresses CAMK1D and downregulates immunosuppressive cytokines IL-10 and TGF-β, reduces Treg infiltration, promotes M1-like macrophages, and increases CD8+ T-cell infiltration and cytotoxicity, while also repressing CREB phosphorylation and stemness regulators.

Sep 30, 2026

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