{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:18Z","timestamp":1792787298730,"version":"4.5.0"},"reference-count":49,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Niles Albright Research Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"https:\/\/ror.org\/0598xrc53","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["R01-CA208205"],"award-info":[{"award-number":["R01-CA208205"]}]},{"name":"National Cancer Institute","award":["R01-CA247441"],"award-info":[{"award-number":["R01-CA247441"]}]},{"name":"National Cancer Institute","award":["R01-CA259253"],"award-info":[{"award-number":["R01-CA259253"]}]},{"name":"National Cancer Institute","award":["R01-NS118929"],"award-info":[{"award-number":["R01-NS118929"]}]},{"name":"National Cancer Institute","award":["R21-EB031982"],"award-info":[{"award-number":["R21-EB031982"]}]},{"name":"National Cancer Institute","award":["R35-CA197743"],"award-info":[{"award-number":["R35-CA197743"]}]},{"name":"National Cancer Institute","award":["U01-CA224348"],"award-info":[{"award-number":["U01-CA224348"]}]},{"name":"National Cancer Institute","award":["U01-CA261842"],"award-info":[{"award-number":["U01-CA261842"]}]},{"name":"Harvard Ludwig Cancer Center","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100001767","name":"National Foundation for Cancer Research","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100001767","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union","award":["101141357"],"award-info":[{"award-number":["101141357"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Jane\u2019s Trust Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"https:\/\/ror.org\/05qwakj56","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,8,22]]},"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Antibody-drug conjugates (ADCs) and bispecific antibodies represent a rapidly advancing frontier in oncology, yet the abnormal tumor microenvironment (TME) hinders their delivery and reduces efficacy. Emerging immunomodulatory ADCs (IM-ADCs) demand mechanistic mathematical models that couple drug transport with immune dynamics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Here, we present a mechanistic framework for the delivery of HE-S2 ADC, an anti-programmed cell death ligand 1 (PD-L1) antibody bearing the bifunctional immunomodulator D18. Our model integrates cancer-immune cells interactions, TME properties, such as dysfunctional vessels, elevated interstitial fluid pressure, tissue hydraulic conductivity, and vascular permeability, spatiotemporal distributions across growing tumor and adjacent host tissue, convective-diffusive transport, ADCs binding and internalization kinetics and tumor-draining lymph node biology governing antigen presentation and the generation of effector CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Parameters were calibrated simultaneously with the murine MC38 and B16 tumor growth data and effector CD8+T\u2009cell data following treatment with D18, anti-PD-L1, and ADC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our mechanistic spatiotemporal model captures the superior antitumor efficacy of the HE-S2 ADC relative to its individual components and provides mechanistic predictions for unmeasured variables, such as spatiotemporal dynamics of drug\/immune-cell distributions. It explains reduced intratumoral D18 exposure via rapid clearance, while antibody\/ADC achieves higher tumor retention through leaky tumor vasculature. The model suggests a reinforcing loop in which improved ADC exposure enhances CD8+T\u2009cell infiltration, driving tumor shrinkage that lowers fluid pressure and improves drug delivery. Parametric analyses findings support TME normalization strategies that increase functional vessel density prior to ADC administration; however, such approaches should preserve sufficient vascular permeability by maintaining vessel pore radius &gt;~40\u2009nm, ensuring pores remain large enough for ADC extravasation and effective intratumoral delivery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The proposed mechanistic model successfully captures how TME properties regulate the delivery and efficacy of IM-ADCs while suggesting TME normalization as a potential strategy to improve treatment outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-015357","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T11:30:30Z","timestamp":1788262230000},"page":"e015357","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic modeling of tumor immune microenvironment reveals strategies to enhance antibody-drug conjugates\u2019 efficacy"],"prefix":"10.1136","volume":"14","author":[{"given":"Constantinos","family":"Harkos","sequence":"first","affiliation":[{"name":"Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance L","family":"Munn","sequence":"additional","affiliation":[{"name":"Edwin L. 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