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This study aimed to overcome this limitation by targeting a potential chemotherapy-resistant immune cell reservoir.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      By using the murine acutely resolved lymphocytic choriomeningitis virus (LCMV) infection and tumor models (colorectal cancer and melanoma), we characterized the susceptibility of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>TST<\/jats:sub>\n                      and virus-specific bystander memory CD8\n                      <jats:sup>+<\/jats:sup>\n                      T (T\n                      <jats:sub>BYS<\/jats:sub>\n                      ) cells to platinum-based chemotherapy-induced cytotoxicity. We next evaluated the antitumor efficacy and underlying mechanisms of combined chemotherapy and T\n                      <jats:sub>BYS<\/jats:sub>\n                      cell-targeted oncolytic virus therapy (OV-BYTE) in tumor-bearing mice with prior LCMV infection or SARS-CoV-2 vaccination. Finally, we assessed the antitumor efficacy of the triple combination regimen (including OV-BYTE, chemotherapy, and PD-1 ICB) in both murine colorectal cancer model and patient-derived colorectal cancer organoid.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We first demonstrated that within the tumor microenvironment, CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>TST<\/jats:sub>\n                      cells are highly susceptible to platinum-based chemotherapy, whereas CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>BYS<\/jats:sub>\n                      cells constitute a quiescent, chemo-resistant population. Leveraging this, CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>BYS<\/jats:sub>\n                      -targeted OV-BYTE therapy synergized with chemotherapy to control tumorigenesis in multiple murine models. Mechanistically, this dual combination directly engaged the CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>BYS<\/jats:sub>\n                      cell reservoir for tumor killing, which was accompanied by the restoration of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>TST<\/jats:sub>\n                      cell function via reduced apoptotic susceptibility and acquisition of a polyfunctional, effector-like state. Consequently, integrating OV-BYTE into the standard chemo-PD-1 ICB regimen resulted in improved antitumor efficacy in both preclinical and patient-derived tumor models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our study establishes the chemotherapy-resistant CD8\n                      <jats:sup>+<\/jats:sup>\n                      T\n                      <jats:sub>BYS<\/jats:sub>\n                      cell niche as a pivotal therapeutic target. By engaging this target, OV-BYTE emerges as a potent combinatorial agent that successfully circumvents a core limitation of standard chemo-immunotherapy, thus offering a rationally designed and translatable strategy to advance combination cancer therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2026-014897","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T14:00:17Z","timestamp":1772632817000},"page":"e014897","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Oncolytic virotherapy potentiates chemo-PD-1 immunotherapy by engaging chemo-resistant bystander CD8\n                    <sup>+<\/sup>\n                    T cells"],"prefix":"10.1136","volume":"14","author":[{"given":"Yang","family":"Yang","sequence":"first","affiliation":[{"name":"Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory 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