{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE335nnn/GSE335282/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE335282"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Empowering macrophage to bridge innate and adaptive antitumor immunity through dual targeting of PCSK9 and innate immune checkpoint","description":"Macrophage-directed immunotherapy has emerged as a promising strategy to eliminate tumors by unleashing phagocytosis, exemplified by blockade of the CD47-SIRPα “don’t eat me” axis. However, despite robust enhancement of phagocytosis, such approaches often fail to generate durable antitumor immunity in solid tumors, highlighting a critical disconnect between innate immune activation and effective T cell responses. Here, we identify PCSK9 as an adaptive resistance factor induced by macrophage immune checkpoint blockade. Tumor-derived PCSK9 promotes lysosomal degradation of MHC-I in macrophages, thereby impairing antigen cross-presentation and limiting CD8⁺ T cell priming. This previously unrecognized mechanism reveals how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this resistance, we engineered bispecific fusion proteins that concurrently target the CD47-SIRPα phagocytosis checkpoint and the PCSK9–MHC-I antigen presentation axis, among which SIRPαD1-αPCSK9 emerged as the optimal format. Dual targeting synergistically enhances macrophage phagocytosis, preserves antigen cross-presentation capacity, and reprograms the tumor microenvironment toward an immunostimulatory state. Consequently, SIRPαD1-αPCSK9 elicits robust activation of both innate and adaptive antitumor immunity, leading to potent tumor control with improved safety. These findings uncover a novel mechanism of resistance to macrophage-centered immunotherapy and establish a rational dual-targeting strategy that bridges phagocytosis and T cell activation, offering a new paradigm for macrophage-driven cancer immunotherapy.","dates":{"publication":"2026/06/17"},"accession":"GSE335282","cross_references":{"GSM":["GSM9809377","GSM9809378","GSM9809375","GSM9809376","GSM9809379"],"GPL":["24247"],"GSE":["335282"],"taxon":["Mus musculus"]}}