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Updated: Apr 12, 2026
Monitoring the Cancer-Immunity Cycle and Exploring Tumor Microenvironment Dynamics
Published on: June 7, 2024
Nano-immunomodulators co-activate immunogenic cell death and the cGAS-STING pathway for breast cancer immunotherapy
Qingqing Huang1, Nana Feng1, Xianghui Cao1
1State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin 300071, China.
Abstract:
Breast cancer generally does not respond to immunotherapy due to its inherently low immunogenicity and insufficient coordination between innate and adaptive immune responses. Here, we demonstrated that concurrent activation of immunogenic cell death (ICD) and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway synergistically amplifies antitumor immunity by promoting dendritic cell maturation, co-stimulatory signaling, and T cell priming. Building on these mechanistic insights, we designed a nanoparticle-based immunomodulator (nanoIM) that integrates a serum albumin-metal core with an endoplasmic reticulum (ER)-targeting polymer shell. Within the tumor microenvironment (TME), nanoIM induces ER stress-mediated ICD and simultaneously releases Mn2+ or Zn2+ ions to activate the cGAS-STING pathway, thereby bridging innate and adaptive immune activation. Systemic administration of nanoIM in breast cancer-bearing mice elicited potent T cell infiltration, robust tumor regression, prolonged survival, and effective prevention of metastasis and recurrence. This study uncovers the molecular crosstalk between ICD and cGAS-STING signaling and establishes a nanomaterial-based strategy for durable and systemic immune activation in breast cancer immunotherapy.
Insights
This study shows that combining immunogenic cell death (ICD) with the cGAS-STING pathway enhances breast cancer immunotherapy. A novel nanoparticle effectively activates both pathways, leading to significant tumor regression and improved survival in mice.
Area of Science:
- Oncology
- Immunology
- Materials Science
Background:
- Breast cancer typically exhibits low immunogenicity, hindering effective immunotherapy responses.
- Current immunotherapies face challenges due to poor coordination between innate and adaptive immune responses.
Purpose of the Study:
- To investigate the synergistic effects of activating immunogenic cell death (ICD) and the cGAS-STING pathway on antitumor immunity in breast cancer.
- To develop a nanoparticle-based immunomodulator (nanoIM) for enhanced breast cancer immunotherapy.
Main Methods:
- Designed a nanoparticle (nanoIM) with a serum albumin-metal core and ER-targeting shell.
- nanoIM was administered systemically to breast cancer-bearing mice.
- Evaluated nanoIM's ability to induce ICD and activate the cGAS-STING pathway within the tumor microenvironment (TME).
Main Results:
- Concurrent activation of ICD and cGAS-STING pathway synergistically amplified antitumor immunity.
- nanoIM treatment promoted dendritic cell maturation, co-stimulatory signaling, and T cell priming.
- Systemic nanoIM administration resulted in significant tumor regression, prolonged survival, and prevention of metastasis and recurrence in mice.
Conclusions:
- Concurrent ICD and cGAS-STING pathway activation is a viable strategy to overcome breast cancer's low immunogenicity.
- The developed nanoIM effectively bridges innate and adaptive immune activation for durable and systemic antitumor effects.
- This research establishes a promising nanomaterial-based platform for advancing breast cancer immunotherapy.
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