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Adv."],"published-print":{"date-parts":[[2026,9,25]]},"abstract":"<jats:p>\n                    Allosteric modulators offer opportunities for pathway-selective G protein\u2013coupled receptor (GPCR) signaling, but the mechanisms enabling biased allosteric modulation remain poorly understood. We identify a helix 8\u2013proximate allosteric site in the immune-metabolic receptor GPR84 and define how it achieves G\n                    <jats:sub>i<\/jats:sub>\n                    -biased signaling. Cryo\u2013electron microscopy structures of the GPR84-G\n                    <jats:sub>i<\/jats:sub>\n                    complexes bound to the orthosteric agonist OX04539 alone or with the positive allosteric modulator PSB-16671 reveal a helix 8\u2013proximate allosteric site for PSB-16671 formed between transmembrane helices 1 (TM1) and TM7. Molecular dynamics simulations and mutagenesis uncover a polar interaction network linking orthosteric and allosteric sites through conserved residues including Asp66\n                    <jats:sup>2.50<\/jats:sup>\n                    , Asn104\n                    <jats:sup>3.36<\/jats:sup>\n                    , and Asn362\n                    <jats:sup>7.45<\/jats:sup>\n                    , and disrupting this network enhances allosteric cooperativity. PSB-16671 stabilizes a receptor conformation with pronounced TM6 displacement that favors G\n                    <jats:sub>i<\/jats:sub>\n                    coupling while disfavoring \u03b2-arrestin recruitment, sustaining macrophage phagocytosis of cancer cells without the desensitization induced by balanced agonists. Sequence analysis suggests that receptor-specific helix 8\u2013proximate allosteric sites may be broadly targetable across class A GPCRs. 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