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In this study, we showed that higher polyacrylamide hydrogels (PAAG) stiffness resulted in the progression and immune escape of PCa via integrin \u03b21\/FAK\/YAP axis. The translocation of YAP into cell nucleus to bind to TEAD2 promoted the transcriptional activation of USP8. NBR1 could be ubiquitinated, and then degraded, via interacting with P62\/SQSTM1 and through autophagy-lysosome pathway. Increased expression of USP8 promoted the abundance of NBR1 via K63-linked de-ubiquitination and PD-L1 via K48-linked de-ubiquitination in response to high PAAG stiffness. NBR1-mediated selective autophagy accelerated the degradation of MHC-1 of PCa. The USP8 inhibitor presented a potential application value in sensitizing immunotherapy of PCa. Taken together, we identified a USP8-mediated de-ubiquitination mechanism that involves in the process of high PAAG stiffness-mediated high expression of PD-L1 and low expression of MHC-1 of PCa cells, which provided a rationale of immunotherapy sensitization of PCa via USP8 inhibition.<\/jats:p>","DOI":"10.1038\/s41419-025-07736-4","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T14:21:54Z","timestamp":1748010114000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Mechanical signal modulates prostate cancer immune escape by USP8-mediated ubiquitination-dependent degradation of PD-L1 and MHC-1"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7563-7781","authenticated-orcid":false,"given":"Zhi-Bin","family":"Ke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Yin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ting","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu-Yun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Ning","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7243-4428","authenticated-orcid":false,"given":"Shao-Hao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Jian","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7426-6501","authenticated-orcid":false,"given":"Qing-Shui","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5324-3733","authenticated-orcid":false,"given":"Yong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6461-7435","authenticated-orcid":false,"given":"Xue-Yi","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7909-7025","authenticated-orcid":false,"given":"Ning","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"7736_CR1","doi-asserted-by":"publisher","first-page":"409","DOI":"10.3322\/caac.21731","volume":"72","author":"KD Miller","year":"2022","unstructured":"Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, et al. 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