A Review of the Cannabinoid Signalling Network in Macrophages and Immunomodulation Opportunities for Tuberculosis Host-Directed Therapy

Mycobacterium tuberculosis survives within macrophages by blocking phagosome maturation, reprogramming host bioenergetics toward a quiescent, lipid-laden state, and redirecting cell death toward necrosis. Host-directed therapy (HDT) targets these subversions rather than the pathogen itself. The endocannabinoidome (eCBome) extends the classical endocannabinoid system to a wider family of bioactive lipid mediators and receptors governing macrophage pathways dysregulated by tuberculosis (TB). Within the eCBome, cannabinoid receptor 2 (CB2) engagement is double-edged: it lowers cyclic adenosine monophosphate (cAMP)-dependent signaling and nuclear factor κB (NF-κB) activity, thereby suppressing tumor necrosis factor α (TNF-α) and interleukin (IL)-12, which sustain granuloma integrity and the interferon-γ responses that license macrophage killing. Paracannabinoids such as palmitoylethanolamide and oleoylethanolamide act independently of cannabinoid receptor 1 (CB1) through peroxisome proliferator-activated receptor α (PPARα), offering a plausible lever against the foamy macrophage phenotype that feeds persistent bacilli. Three mutually non-exclusive HDT opportunities therefore emerge: enhancing intracellular clearance, resolving pathological inflammation, and restoring metabolic homeostasis. Support for each differs markedly, and realizing any of them requires resolving CB2 selectivity, cytochrome P450-mediated interactions with rifampicin, and immunosuppression risk in HIV-coinfected populations; divergent regulatory frameworks and a substantial gap in direct TB-specific evidence remain further obstacles.