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Notably, the majority of approved immunotherapies do not target antigen processing and presentation, which are key steps in the development of immune responses and harbor potential as targets to improve immunotherapy. Here, we demonstrate that breast tumors induce locoregional lymph node impairment in antigen presentation\u2014but not in antigen processing\u2014which limits anti-cancer antigen- specific T cell responses. Inhibition of the locoregional T cell response was due to a tumor-mediated reduction of the cytokine IL1\u03b2 in tumor draining lymph nodes, which impaired antigen presentation. Further, we tested the ability of dendritic cells in lymph nodes at various distances from the primary tumor to be activated utilizing an antigen- agnostic adjuvant delivery strategy. We observed improved anti-tumor T cell responses when the adjuvant was delivered to cancer antigen-positive lymph nodes distant from the tumor, suggesting these lymph nodes can be targeted to improve anti-cancer immune responses. When combined with immune checkpoint blockade, delivery of the adjuvant to distant lymph nodes led to long-term survival and protection from recurrence. Antigen presentation and T cell responses could also be recovered by exogenous delivery of IL1\u03b2 via intratumoral injection, with improved survival when combined with immune checkpoint blockade. Our study demonstrates that tumor- induced locoregional impairment of antigen presentation can be overcome by the appropriate introduction of immunological adjuvant to tumor-distant lymph nodes or by restoring IL1\u03b2 to the tumor-draining lymph node. These strategies can induce high- quality, durable immune responses and have clinical implications for expanding the efficacy of immunotherapies.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>Breast tumors induce locoregional lymph node impairments in antigen presentation, which can be remedied via either IL1\u03b2 delivery or antigen-agnostic adjuvant therapies to distant lymph nodes, facilitating better immunotherapy responses.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.17.676884","type":"posted-content","created":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T16:30:16Z","timestamp":1758385816000},"source":"Crossref","is-referenced-by-count":0,"title":["Overcoming impaired antigen presentation in tumor draining lymph nodes facilitates immunotherapy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2223-1849","authenticated-orcid":false,"given":"Meghan J.","family":"O\u2019Melia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3816-6255","authenticated-orcid":false,"given":"Lutz","family":"Menzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2539-5179","authenticated-orcid":false,"given":"Pin-Ji","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9948-7909","authenticated-orcid":false,"given":"Hengbo","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neian","family":"Contreras-Alvarado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8764-2350","authenticated-orcid":false,"given":"Johanna J.","family":"Rajotte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3904-478X","authenticated-orcid":false,"given":"Lingshan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4648-7067","authenticated-orcid":false,"given":"Mohammad R.","family":"Nikmaneshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4442-4668","authenticated-orcid":false,"given":"James W.","family":"Baish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7855-9125","authenticated-orcid":false,"given":"Jessalyn M.","family":"Ubellacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7522-6173","authenticated-orcid":false,"given":"Genevieve M.","family":"Boland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0172-5620","authenticated-orcid":false,"given":"Sonia","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0698-7232","authenticated-orcid":false,"given":"Lance L.","family":"Munn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3453-9384","authenticated-orcid":false,"given":"Timothy P.","family":"Padera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025092313550672000_2025.09.17.676884v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21820"},{"key":"2025092313550672000_2025.09.17.676884v1.2","doi-asserted-by":"crossref","unstructured":"Debien V , De Caluw\u00e9 A , Wang X , Piccart-Gebhart M , Tuohy VK , Romano E , et al. 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