{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE303nnn/GSE303940/"]},"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=GSE303940"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"XIAP-coordinated PKC signaling overcomes immunotherapy resistance via immunogenic rewiring to empower therapeutic rechallenge [RNA-Seq]","description":"Immune-checkpoint blockade (ICB) against PD-1/PD-L1 has transformed cancer care, yet primary and acquired resistance limit its reach. By profiling substrate-based protein kinase C (PKC) activity, rather than pan-PKC expression, we uncover a superior biomarker predicting survival and anti-PD-1 responsiveness in non-small cell lung cancer (NSCLC). Critically, pharmacological pan-PKC inhibition overcomes anti-PD-1 resistance across diverse preclinical models through a coordinated immunologic program. Specifically, PKC blockade triggers Caspase-3/GSDME-dependent immunogenic cell death (ICD) with ATP/HMGB1 release. It concurrently reprograms the tumor microenvironment (TME) by enriching CD8+ T cells and regulatory T cells (Tregs) in a CCR5-dependent manner, while inducing tumor-intrinsic PD-L1 degradation to sustain CD8+ T cell function. Mechanistically, targeting PKC destabilizes XIAP, whose degradation not only unleashes caspase-mediated ICD and PD-L1 degradation but also licenses CCL4 secretion for CCR5-centric TME rewiring. Importantly, PKC blockade synergizes exclusively with anti-CTLA4 by selectively depleting intratumoral Tregs, providing a rational rechallenge regimen for anti-PD-1-refractory malignancies. Our findings establish PKC activity as a crucial biomarker and validate PKC inhibition as a translatable strategy to dismantle ICB resistance.","dates":{"publication":"2026/05/16"},"accession":"GSE303940","cross_references":{"GSM":["GSM9139310","GSM9139308"],"GPL":["24247"],"GSE":["303940"],"taxon":["Mus musculus"]}}