{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T02:01:55Z","timestamp":1781143315078,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,8]]},"group-title":"Cancer Biology","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NCI","award":["2R01CA102363"],"award-info":[{"award-number":["2R01CA102363"]}]},{"DOI":"10.13039\/100015194","name":"Feist-Weiller Cancer Center","doi-asserted-by":"crossref","award":["149741524A"],"award-info":[{"award-number":["149741524A"]}],"id":[{"id":"10.13039\/100015194","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>\n                    Resistance to immunotherapy remains a major clinical challenge in\n                    <jats:italic>TP53<\/jats:italic>\n                    -mutant head and neck squamous cell carcinoma (HNSCC), a disease subset characterized by immune exclusion, high recurrence, and poor outcomes. Given the constitutive activation of PI3K\/AKT\/mTOR signaling in\n                    <jats:italic>TP53<\/jats:italic>\n                    -mutant HNSCC and its role in disease progression, we investigated whether the mTOR inhibition (mTORi) could overcome immune resistance and improve outcomes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We evaluated the effects of mTOR inhibitor everolimus in\n                    <jats:italic>TP53<\/jats:italic>\n                    -mutant, anti-PD-1-resistant syngeneic HNSCC cell lines and syngeneic tumor models. Tumor microenvironment (TME) changes, including immune cell infiltration, immune checkpoint expression, and key pathways associated with immune suppression and angiogenesis were assessed to define the mechanisms underlying TME remodeling.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Everolimus significantly suppressed tumor growth in syngeneic HNSCC models. At the cellular level, everolimus significantly increased intratumoral CD8+ T cell and dendritic cell (DC) infiltration while reducing the accumulation of regulatory T cells (Tregs). Mechanistically, everolimus induced a cytokine\/chemokine response, marked by increased TNF-\u03b1\/CXCL10 expression, leading to enhanced immune infiltration. Everolimus also inhibited the HIF-1\u03b1\/VEGFA angiogenic axis, a central driver of immune exclusion and myeloid-derived suppressor cell (MDSC) recruitment. Furthermore, everolimus treatment attenuated PD-1\/PD-L1 signaling by reducing PD-1 and PD-L1 expression, respectively, in T cells and tumor cells, thereby restoring T-cell cytotoxic competence.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>\n                    These findings demonstrate that mTORi with everolimus reverses multiple mechanisms of immune resistance in\n                    <jats:italic>TP53<\/jats:italic>\n                    -mutant HNSCC by promoting immune cell recruitment, suppressing immunosuppressive pathways, and enhancing anti-tumor T cell activity. Collectively, these results support mTORi as a mechanistically rational strategy for reprogramming immune resistance in\n                    <jats:italic>TP53<\/jats:italic>\n                    -mutant HNSCC and provide a strong preclinical rationale for combining everolimus with immune therapy in patients who are likely to fail immunotherapy.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.04.730026","type":"posted-content","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T03:55:15Z","timestamp":1780977315000},"source":"Crossref","is-referenced-by-count":0,"title":["mTOR inhibition augments antitumor immune effector response by reprogramming the\n                  <i>TP53<\/i>\n                  -mutant, immune-cold HNSCC tumor microenvironment"],"prefix":"10.64898","author":[{"given":"Priyatosh","family":"Nath","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health, Shreveport, Louisiana-71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alok","family":"Khandelwal","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health, Shreveport, Louisiana-71103, USA"},{"name":"Feist-Weiller Cancer Center, Louisiana State University Health Shreveport, Shreveport, LA 71103"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health, Shreveport, Louisiana-71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara","family":"Moore-Medlin","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health, Shreveport, Louisiana-71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srivatsa Surya","family":"Vasudevan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health, Shreveport, Louisiana-71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor Albornoz","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health, Shreveport, Louisiana-71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar E.","family":"Franco","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Louisiana State University Health, Shreveport, Louisiana-71103, USA"},{"name":"Feist-Weiller Cancer Center, Louisiana State University Health Shreveport, Shreveport, LA 71103"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Silvio","family":"Gutkind","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, California-92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cherie-Ann O.","family":"Nathan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health, Shreveport, Louisiana-71103, USA"},{"name":"Feist-Weiller Cancer Center, Louisiana State University Health Shreveport, Shreveport, LA 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