Citation: Xiu Pan, Kai-Hui Yan, Meng-Die Wang, Ling-Xiao Zhou, Kun-Mei Liu, Jin-Yu An, Yan Jiang, Shun Feng, Ming-Yu Wu. Boosting tumor retention via water solubility and molecular charge engineering for enhanced photoimmunotherapy[J]. Chinese Chemical Letters, ;2026, 37(12): 112291. doi: 10.1016/j.cclet.2025.112291 shu

Boosting tumor retention via water solubility and molecular charge engineering for enhanced photoimmunotherapy

Xiu Pan ^{a, b} ,
Kai-Hui Yan ^a ,
Meng-Die Wang ^a ,
Ling-Xiao Zhou ^a ,
Kun-Mei Liu ^a ,
Jin-Yu An ^a ,
Yan Jiang ^{d, *,} ,
Shun Feng ^{a, *,} ,
Ming-Yu Wu ^{a, c, *,}

a.
Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
b.
Key Laboratory of Advanced Technologies of Material, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
c.
College of Biomedical Engineering, Sichuan University, Chengdu 610065, China
d.
Department of Nursing, West China Hospital/West China School of Nursing, Sichuan University, Chengdu 610041, China

hxhljy2018@163.com

fengshunxd@hotmail.com

wumy@scu.edu.cn

Received Date: 22 September 2025
Revised Date: 15 December 2025
Accepted Date: 16 December 2025
Available Online: 16 December 2025

Figures(7)

Photon-activated immunogenic cell death (ICD) is a promising anti-tumor immunotherapy strategy, offering a new avenue for combating cancer recurrence and metastasis. Nevertheless, the poor tumor retention of ICD inducers, such as photosensitizers (PSs), which results in insufficient immune activation, hinders both immediate efficacy and long-term outcomes. To address this challenge, we designed a series of PSs via structural engineering of the thiophenopyridine-based donor-acceptor (D-A) framework, optimizing water solubility and molecular charge. The structure-activity relationship revealed that increasing water solubility and reducing positive charge minimized protein adsorption, thereby evading immune clearance and prolonging tumor retention. Notably, LTD-PEG7 exhibited prolonged retention exceeding 96 h. The oligomerized glycol unit formed a “protective hydration layer” that shields the PS from protein adsorption, while its amphiphilic character enhances cellular uptake. Giving the excellent type I reactive oxygen species (ROS) generation efficiency, LTD-PEG7 could efficiently overcome hypoxia-induced immunosuppression in the tumor microenvironment. Furthermore, the ROS mediated mitochondrial damage, triggering potent anti-tumor immune responses through ICD and ultimately eliciting a robust systemic anti-tumor immune response that significantly curbs the proliferation of 4T1 tumors in vivo. This study provides a valuable design principle for developing long-term tumor-retentive PS and advances photoimmunotherapy strategies.
- Tumor retention,
- Photoimmunotherapy,
- Water solubility,
- Molecular charge,
- Immunogenic cell death
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