{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:07:47Z","timestamp":1788754067789,"version":"build-2803163510"},"reference-count":60,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cancer and autoimmune diseases are traditionally regarded as distinct clinical entities, yet growing evidence indicates that both arise from dysregulation of shared immune\u2010regulatory pathways coordinating immune activation, peripheral tolerance and tissue homeostasis. Rather than acting as independent processes, immune checkpoint signalling, T\u2010cell functional integrity, regulatory T\u2010cell (Treg) stability, cytokine and myeloid\u2010cell polarization, and spatial immune organization form interconnected circuits that determine the quality, magnitude, and persistence of immune responses. The direction and extent of perturbation within these pathways, rather than simple activation or inhibition, determines whether immune responses promote tumour evasion or autoimmunity. Clinical experience with immune checkpoint inhibitors provides compelling evidence for this shared biology: blockade of PD\u20101 or CTLA\u20104 restores antitumor immunity but frequently disrupts peripheral tolerance, producing immune\u2010related adverse events that closely resemble spontaneous autoimmune disease, showing checkpoints function within a broader network balancing protective immunity with self\u2010tolerance. In this review, we propose the immune rheostat as an integrative framework unifying these shared mechanisms across cancer and autoimmune disease. We examine checkpoint co\u2010signalling, T\u2010cell exhaustion, Treg epigenetic stability, cytokine\/myeloid networks, spatial architecture, and biomarker signatures across the disease spectrum, illustrated through a lupus nephritis model in which restoring follicular regulatory (Tfr)\u2010helper (Tfh) T\u2010cell balance demonstrates how coordinated pathway rewiring restores homeostasis. This review offers a unified framework for shared immune regulation, proposes layer\u2010specific therapeutic strategies and a matched, non\u2010checkpoint\u2010restricted biomarker panel for tracking patients along the rheostat, and situates this framework against related single\u2010disease and checkpoint\u2010centric models.<\/jats:p>","DOI":"10.1111\/imm.70198","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T03:20:42Z","timestamp":1788751242000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Immune Rheostat: A Shared Regulatory Axis Linking Cancer Immune Evasion and Autoimmune Activation"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0881-575X","authenticated-orcid":false,"given":"Sivasangari","family":"Balakrishnan","sequence":"first","affiliation":[{"name":"Independent Researcher  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3798-2899","authenticated-orcid":false,"given":"Karthi","family":"Muthuswamy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Bharathiar University  Coimbatore India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1203486"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200108023450506"},{"key":"e_1_2_16_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577\u2010019\u20100176\u20101"},{"key":"e_1_2_16_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239"},{"key":"e_1_2_16_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.05.009"},{"key":"e_1_2_16_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862"},{"key":"e_1_2_16_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665\u20109913(20)30444\u20103"},{"key":"e_1_2_16_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1703481"},{"key":"e_1_2_16_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15050557"},{"key":"e_1_2_16_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.01.022"},{"key":"e_1_2_16_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202521355"},{"key":"e_1_2_16_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010026\u201000934\u2010y"},{"key":"e_1_2_16_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2023.102283"},{"key":"e_1_2_16_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590\u2010018\u20100051\u20100"},{"key":"e_1_2_16_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010022\u201000520\u20105"},{"key":"e_1_2_16_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010019\u20101914\u20108"},{"key":"e_1_2_16_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.108"},{"key":"e_1_2_16_19_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200057"},{"key":"e_1_2_16_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.36"},{"key":"e_1_2_16_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.08.039"},{"key":"e_1_2_16_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.05.001"},{"key":"e_1_2_16_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010019\u20100116\u2010x"},{"key":"e_1_2_16_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adg0675"},{"key":"e_1_2_16_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035"},{"key":"e_1_2_16_26_1","first-page":"326","article-title":"Subsets of Exhausted T Cells","volume":"20","author":"Miller B. 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