Macrophage-mesenchymal crosstalk in recurrent glioblastoma: a perspective for therapeutic strategies.

Abstract

Glioblastoma (GBM) remains one of the most lethal cancers, with recurrence in nearly all patients despite standard therapy. However, the biological mechanisms governing recurrence remain incompletely understood. Increasing evidence suggests that recurrence is driven not only by tumor-intrinsic resistance, but also by dynamic reciprocal interactions between tumor cell plasticity and the tumor microenvironment (TME). Here, we integrate these dynamic interactions into a unifying ecological framework in which therapeutic stress induces proneural-to-mesenchymal transition (PMT), a phenotypic shift associated with increased invasiveness, inflammatory signaling, and treatment tolerance. Mesenchymal tumor states remodel the TME by promoting the recruitment and functional reprogramming of monocyte-derived macrophages (MDMs), which become increasingly enriched in recurrent tumors. In turn, macrophage-derived cytokines, including IL-6 and TGF-β, together with metabolites such as lactate and cholesterol derivatives, reinforce mesenchymal transcriptional programs and stabilize tumor cell states through immunometabolic interactions. We highlight how this bidirectional crosstalk forms a macrophage-mesenchymal feedback loop that sustains the recurrent tumor ecosystem. Fundamentally metabolism acts as a key regulatory layer that links immune polarization to tumor cell plasticity. Finally, we outline therapeutic strategies aimed at disrupting this circuit, emphasizing combination approaches that concurrently target phenotypic plasticity, macrophage recruitment and function, and metabolic crosstalk. A circuit-informed perspective provides a conceptual basis for designing more effective interventions against recurrent GBM.