Self-transforming hydrogel mimicking tertiary lymph nodes to activate cGAS-STING pathway for enhanced antitumor immunotherapy

Sep 30, 2026

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Tertiary lymph node (TLS)–inducing drugs can cause autoimmune risks due to nonspecific distribution. A self-transforming chitosan hydrogel was developed as a biomimetic TLS by peritumoral injection into bacteria-colonized tumors, followed by rapid in situ gelation. After doxorubicin and cefotaxime kill tumor cells and intratumoral bacteria, the hydrogel adsorbs bacterial PAMPs, DAMPs, and tumor antigens. These danger signals recruit immune cells, activate dendritic cells via DNA-mediated cGAS-STING, remodel the immunosuppressive microenvironment, and suppress tumor growth and metastasis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Antitumor immunity and tumor microenvironment constraints

TLSs: roles, formation limits, and heterogeneity

Rationale for biomimetic TLS activation

MATERIALS SCIENCE Self-transforming hydrogel mimicking tertiary lymph nodes to activate cGAS-STING pathway for enhanced antitumor immunotherapy Fei Wang1, Yukun Zeng2, Manqi Yan1, Ziqi Zhou1, Lingzi Feng1, Fei Yang3*, Wei Zhao4*, Yong Hu1* The nonspecific distribution of tertiary lymph node (TLS)–inducing drugs may trigger autoimmune diseases. We developed a self-transforming chitosan hydrogel to act as a biomimetic TLS. The chitosan hydrogel solution was peritumorally injected in bacteria-colonized tumors in mice followed by the rapid in situ gelation. After killing tumor cells and intratumoral bacteria by doxorubicin and cefotaxime, the hydrogel efficiently adsorbed bacterial pathogen-associated molecular patterns, tumor cell–derived damage-associated molecular patterns, and tumorassociated antigens. These danger signals greatly potentiated immune cell recruitment into the hydrogel and sufficiently activated dendritic cells (DCs) by the absorbed DNA-mediated cGAS-STING activation. The activated DCs converted T cells into cytotoxic T cells, and these activated immune cells migrated through the pores of hydrogels into the tumor tissues, effectively remodeling the immunosuppressive microenvironment, thereby inhibiting the tumor growth and metastasis. These findings demonstrate a previously unidentified method to establish a safe, easy-to-control, and effective biomimetic TLS that offers a promising strategy for updating current combined immunotherapy against various tumors. copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) . INTRODUCTION Antitumor immunity harnesses the immune system to specifically kill tumor cells while establishing long-term immune surveillance to prevent tumor recurrence, which pioneers a new landscape for antitumor treatment (1–4) . Nevertheless, the tumor microenvironment exhibits poorly differentiated vasculature, leading to inadequate supply of nutrients and oxygen, as well as the accumulation of waste products (5) . This harsh environment forces immune cells to compete with tumor cells for nutrients, causing metabolic adaptations of immune cells that impair their effector functions (6, 7) . Besides, the immunosuppressive molecule PDL1 (programmed death ligand 1) expressed on tumor cells can interact with T cells and further induce T cell exhaustion. Furthermore, accumulated evidence indicated that specific intratumoral bacteria can exacerbate the immunosuppressive microenvironment and even accelerate tumor metastasis (8–10) . Collectively, the immunosuppressive tumor microenvironment severely limits the efficacy of antitumor immunity. Researchers aim to transform immunosuppressive “cold” tumors into immunoactive “hot” tumors to enhance the effectiveness of antitumor immunotherapy, and studies have shown that treatments such as photothermal therapy, radiotherapy, chemotherapy, and the delivery of immune checkpoint inhibitors and therapeutic antibodies to tumor tissues can facilitate this transition (11–14). Meanwhile, the tumor-associated antigens are released by destroyed tumor cells during these processes. Dendritic cells (DCs) uptake these antigens and migrate to tumor-draining lymph nodes to activate T cells into effector 1college of engineering and Applied Sciences, nanjing University, nanjing 210023, Jiangsu, china. 2the third People’s hospital of Shenzhen, the Second Affiliated hospital, Southern University of Science and technology, 29, Bulan Rd., Shenzhen 518112, china. 3the Affiliated huai’an hospital of Xuzhou Medical University, huai’an Second People’s hospital, huai’an 223002, Jiangsu, china. 4department of clinical laboratory, Women’s hospital of nanjing Medical University (nanjing Women and children’s healthcare hospital), nanjing 210004, china. *[corresponding author.

FAQs

Why can TLS-inducing drugs trigger autoimmune diseases?

Their nonspecific distribution may initiate autoimmune responses.

How does the self-transforming chitosan hydrogel function in the proposed strategy?

It is peritumorally injected into bacteria-colonized tumors and rapidly gels in situ, enabling adsorption of bacterial PAMPs, DAMPs, and tumor antigens after chemotherapy-mediated killing.

What immune activation pathway is central to the hydrogel’s effect?

DNA-mediated cGAS-STING activation in dendritic cells, which then promotes cytotoxic T-cell generation and effective antitumor immune responses.

Sep 30, 2026

Uploaded by Muffet