{"doi":"10.1101/2025.10.28.685116","title":"Dynamic PD-L1 Regulation Shapes Tumor Immune Escape and Response to Immunotherapy","abstract":"Abstract A major challenge in cancer treatment is the ability of tumor cells to adapt to immunotherapy through immune escape, often mediated by the PD-1/PD-L1 pathway. To investigate this, we adapted an ordinary differential equation model of combination therapy, incorporating the dynamics of the immune checkpoint inhibitor Avelumab and the immunostimulant NHS-muIL12. Using literature-derived parameter values from a previous study, we refitted a single parameter across therapies, which showed that PD-L1 expression increased with immunotherapy, while Avelumab blocked its functional signaling, preventing PD-L1 from suppressing T-cell activity. Incorporating therapy-dependent, dynamically regulated PD-L1 expression enabled a biologically grounded mechanism to reproduce experimental observations, leading us to formulate PD-L1 tumor expression as a dynamic variable ( ϵ ) and providing a mechanistic basis for both therapeutic synergy and treatment failure. Our results indicate that tumor resistance is linked to dose-dependent upregulation of PD-L1 following NHS-muIL12 treatment, explaining treatment failure, while PD-1/PD-L1 blockade in combination therapy enables effective anti-tumor immune responses.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":579471,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9472,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1490067,"name":"Aigerim Kalizhanova","orcid":null,"position":1,"is_corresponding":false},{"id":941408,"name":"Aisha Tursynkozha","orcid":null,"position":2,"is_corresponding":false},{"id":1490068,"name":"Denise Dengi","orcid":null,"position":3,"is_corresponding":false},{"id":940822,"name":"Ardak Kashkynbayev","orcid":"0000-0002-1338-2058","position":4,"is_corresponding":false},{"id":331060,"name":"Yang Kuang","orcid":"0000-0003-2774-4133","position":5,"is_corresponding":false},{"id":986563,"name":"Bruce Pell","orcid":"0000-0003-1358-8061","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:58:30.282164Z","pmid":"41279131","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}