Nano-immunomodulators co-activate immunogenic cell death and the cGAS-STING pathway for breast cancer immunotherapy.

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.