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The correlation between PD\u2010L1 expression and ICI effectiveness is uncertain, leaving the role of PD\u2010L1 as a predictive marker for ICI efficacy unclear. Among several ways to enhance the efficacy of ICI, trials are exploring combining ICIs with serine\/threonine\u2010protein kinase mTOR (mTOR) inhibitors in different tumor types. The potential interaction between mTOR inhibitors and PD\u2010L1 expression in UC has not been well characterized. In our study, we investigated how phosphoinositide 3\u2010kinase (PI3K)\/AKT\/mTOR pathway inhibitors (TAK\u2010228, everolimus and TAK\u2010117) affect PD\u2010L1 expression and function in preclinical bladder cancer cell models. TAK\u2010228 increased cell surface levels of glycosylated PD\u2010L1 in all but one of the seven cell lines, regardless of baseline levels. TAK\u2010228 promoted the secretion of epidermal growth factor (EGF) and interferon\u2010\u03b2 (IFN\u03b2), both linked to PD\u2010L1 protein induction. Blocking EGF and IFN\u03b2 receptors reversed the TAK\u2010228\u2010induced PD\u2010L1 increase. Additionally, TAK\u2010228 enhanced IFN\u2010\u03b3\u2010induced PD\u2010L1 expression and intracellular HLA\u2010I levels in some cells. TAK\u2010228\u2010treated bladder cancer cells exhibited resistance to the cytotoxic effects of peripheral blood mononuclear cells (PBMCs) and cluster of differentiation 8 (CD8)+ T\u00a0cells. The addition of an anti\u2010PD\u2010L1 antibody diminished this resistance in T24 cells. Increased expression of PD\u2010L1 under TAK\u2010228 exposure was confirmed in patient\u2010derived explants (PDEs) treated\n                    <jats:italic>ex\u2009vivo<\/jats:italic>\n                    . These preclinical findings suggest that mTOR inhibition with TAK\u2010228 can increase PD\u2010L1 levels, potentially impacting the specific immune response against UC cells. This highlights the rationale for exploring the combination of mTOR inhibitors with ICIs in patients with advanced UC.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13699","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T07:48:18Z","timestamp":1726040898000},"page":"151-172","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Enhancing immunotherapy through\n                    <scp>PD<\/scp>\n                    \u2010\n                    <scp>L<\/scp>\n                    1 upregulation: the promising combination of anti\u2010\n                    <scp>PD<\/scp>\n                    \u2010\n                    <scp>L<\/scp>\n                    1 plus m\n                    <scp>TOR<\/scp>\n                    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