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GCs are indispensable anti-inflammatory drugs yet linking specific ligand\u2013receptor structural states to specific biological outcomes has remained a major barrier to designing safer, more selective therapies. Using structure-based design, we developed selective glucocorticoid receptor modulators (SGRMs) of immune function by extending a steroidal scaffold from the ligand-binding pocket into an adjacent solvent channel. These SGRMs suppressed T cell pro-inflammatory cytokines and promoted differentiation of memory precursor T cells while showing minimal induction of M2 macrophage polarization or T cell checkpoint proteins PD-1 and CTLA-4, all key targets of immunotherapy. Molecular dynamics simulations revealed that solvent-channel substituents function as a lever arm to drive dynamic oscillations in the steroid core, thereby allosterically tuning GR activity states. Systematic perturbation of immune cells with a graded series of ligands enabled a\n                  <jats:italic>l<\/jats:italic>\n                  igand\n                  <jats:italic>\n                    <jats:underline>p<\/jats:underline>\n                  <\/jats:italic>\n                  erturbation with\n                  <jats:italic>\n                    <jats:underline>m<\/jats:underline>\n                  <\/jats:italic>\n                  achine\n                  <jats:italic>l<\/jats:italic>\n                  earning (LPML) framework to map coregulated responses across cell types and identified effector T cell gene networks tightly coupled with immune checkpoint induction. This approach outlines a general strategy for decoding the logic of allosteric drug action, enabling the rational design of SGRMs with tailored immunomodulatory profiles.\n                <\/jats:p>","DOI":"10.64898\/2026.02.02.703046","type":"posted-content","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T23:50:22Z","timestamp":1770249022000},"source":"Crossref","is-referenced-by-count":0,"title":["Selective Glucocorticoid Receptor Modulators of Immune Checkpoint Function"],"prefix":"10.64898","author":[{"given":"Robin R.","family":"Kobylski","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA"},{"name":"Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, La Jolla, CA, 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