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In addition to acting as a barrier to antimicrobial treatments and as a niche for the transmission of antibiotic resistance genes, biofilm-associated extracellular polymeric substances and metabolites modulate innate and adaptive immune responses. With the rise of emerging resistance against last-resort antibiotics, divulging the cross-talk between ESKAPE biofilms and the host immune system is essential for designing therapies aimed at immunoactivation. Compared with their Gram-positive ESKAPE counterparts, limited therapeutics coupled with higher mortality-associated phenotypes make Gram-negative ESKAPE pathogens an urgent priority for immediate action. The ultimate goals for strategizing such interventions are to disrupt biofilm integrity, restore immune efficacy, and improve clinical outcomes against multi- or pan-drug-resistant pathogens. Against this backdrop, this review highlights the alteration of the host immune system and the modifications in innate and adaptive immune responses caused by Gram-negative ESKAPE pathogens. In addition, the possibility of success of immunomodulation-based strategies in combating bacterial biofilms and accentuating the activity of known antimicrobials is discussed objectively.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00374-26","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:27:12Z","timestamp":1790170032000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["The interface of biofilm and immune system for Gram-negative ESKAPE pathogens"],"prefix":"10.1128","volume":"94","author":[{"given":"Shatarupa","family":"Biswas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02tne2741","id-type":"ROR","asserted-by":"publisher"}],"name":"AMR-Research Laboratory, Department of Biological Sciences, Adamas University","place":["Kolkata, 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