The study investigates the induction of fungicidal tolerance in *Cryptococcus neoformans* during fungal meningitis by brain glucose. The research reveals that glucose, a key energy source for the brain, induces fungal tolerance to amphotericin B (AmB) through the activation of the fungal glucose repression activator Mig1. Mig1-mediated tolerance limits the efficacy of AmB in treating cryptococcal meningitis in mice by inhibiting ergosterol synthesis and promoting the production of inositolphosphorylceramide (IPC), which competes with AmB for ergosterol. The combination of AmB with aureobasidin A (AbA), an inhibitor of IPC synthesis, shows improved efficacy against cryptococcal meningitis in mice. These findings highlight the importance of host-derived metabolites in inducing fungicidal tolerance and suggest potential therapeutic strategies to enhance the treatment of fungal meningitis.The study investigates the induction of fungicidal tolerance in *Cryptococcus neoformans* during fungal meningitis by brain glucose. The research reveals that glucose, a key energy source for the brain, induces fungal tolerance to amphotericin B (AmB) through the activation of the fungal glucose repression activator Mig1. Mig1-mediated tolerance limits the efficacy of AmB in treating cryptococcal meningitis in mice by inhibiting ergosterol synthesis and promoting the production of inositolphosphorylceramide (IPC), which competes with AmB for ergosterol. The combination of AmB with aureobasidin A (AbA), an inhibitor of IPC synthesis, shows improved efficacy against cryptococcal meningitis in mice. These findings highlight the importance of host-derived metabolites in inducing fungicidal tolerance and suggest potential therapeutic strategies to enhance the treatment of fungal meningitis.