{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:29:26Z","timestamp":1787614166127,"version":"build-2736575974"},"reference-count":51,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"unspecified","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Jean-Guy Sabourin Research Chair from the Faculty of Pharmacy of Universit\u00e9 de Montr\u00e9al","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100000027","name":"Institute of Cancer Research","doi-asserted-by":"publisher","award":["PJT 180373"],"award-info":[{"award-number":["PJT 180373"]}],"id":[{"id":"10.13039\/501100000027","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ANR, France 2030","award":["ANR-21-RHUS-0010"],"award-info":[{"award-number":["ANR-21-RHUS-0010"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,3,13]]},"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Identifying the mechanisms underlying resistance to immune checkpoint inhibitors (ICIs) has become a major focus in cancer immunotherapy. Our previous work identified\n                      <jats:italic>F2RL1<\/jats:italic>\n                      expression, encoding the G protein-coupled receptor Protease-Activated Receptor-2 (PAR-2), as a negative biomarker of ICIs responsiveness. This study aims to evaluate the therapeutic potential of targeting PAR-2 to overcome resistance to ICIs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Activated PAR-2 levels in patient serum were quantified using a protein-based assay to assess PAR-2 activation and its association with clinical outcomes. The therapeutic impact of PAR-2 targeting was evaluated in preclinical tumor models using either global F2rl1 gene deletion or pharmacological inhibition with the selective, insurmountable PAR-2 negative allosteric modulator I-117, in combination with anti-PD-1 therapy. To further characterize immune changes associated with PAR-2 targeting, immune cell populations, cytokine profiles, and transcriptional programs were analyzed in tumors and\/or tumor-draining lymph nodes (tDLNs). Ex vivo co-culture assays were performed to assess antigen presentation by CD11c\n                      <jats:sup>+<\/jats:sup>\n                      dendritic cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Activated PAR-2 levels were significantly elevated in the serum of patients with cancer across multiple tumor types and were associated with reduced survival in patients with lung cancer treated with pembrolizumab plus platinum-based chemotherapy. In preclinical models, both global F2rl1 deletion and pharmacological inhibition of PAR-2 with I-117 significantly potentiated the therapeutic efficacy of anti-PD-1 treatment. PAR-2 inhibition altered the tumor immune microenvironment, characterized by a reduction in putative immunosuppressive myeloid cell populations and increased activation of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in tumors and tDLNs. These immune changes were accompanied by a cytokine shift favoring T helper 1 (Th1)-type responses and reduced immunosuppressive cytokines. Bulk RNA sequencing of myeloid cells indicated that PAR-2 activity was associated with impaired antigen presentation pathways. Consistently, ex vivo co-culture assays demonstrated that antigen-presenting functions of tumor-associated and draining lymph node CD11c\n                      <jats:sup>+<\/jats:sup>\n                      dendritic cells were significantly enhanced following PAR-2 inhibition with I-117.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support PAR-2 inhibition as a strategy to enhance the efficacy of PD-1 blockade, providing a rationale for their combined use in cancer immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013507","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T15:30:25Z","timestamp":1775230225000},"page":"e013507","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting PAR-2 with a 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