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Despite the extensive exploration of immunotherapy, particularly the anti-programmed cell death protein 1 (anti-PD-1) antibody, in clinical trials, the efficacy remains unsatisfactory. A more profound comprehension of the resistance mechanisms and the development of innovative therapeutic strategies is imperative.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A screening was performed for drugs capable of upregulating major histocompatibility class I (MHC I) expression among clinically common drugs. The effects of the drug on both T cells and tumor cells, as well as its combination efficacy with anti-PD-1 antibody, were studied in vitro and in vivo osteosarcoma models. The molecular mechanisms underlying these biological processes were explored via RNA sequencing analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Etoposide was shown to upregulate the MHC I expression in osteosarcoma cells, thereby enhancing the cytotoxicity of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Interleukin-33 (IL-33) played a dominant role in etoposide-activated anti-tumor immune response. Etoposide promoted the secretion of IL-33 and augmented the expression of IL-33 binding suppression of tumorigenicity 2 (ST2) receptor, which activated the nuclear factor kappa-B signaling pathway and resulted in MHC I upregulation. Furthermore, etoposide was demonstrated to improve the therapeutic efficacy of anti-PD-1 antibody.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study revealed the molecular mechanism underlying etoposide-activated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell anti-tumor immunity. The combination of Etoposide and anti-PD-1 antibody has the potential to benefit patients with advanced osteosarcoma.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012591","type":"journal-article","created":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T12:55:23Z","timestamp":1766321723000},"page":"e012591","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Etoposide activates CD8\n                    <sup>+<\/sup>\n                    T cell anti-tumor immunity in osteosarcoma through MHC I upregulation via tumor-secreted IL-33 mediated signaling"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9881-7806","authenticated-orcid":false,"given":"Xin","family":"He","sequence":"first","affiliation":[{"name":"Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, 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