The intricate cross-talks between tumor cells and their microenvironment play a key role in cancer progression and resistance to treatment. In recent years, targeting pro-tumorigenic components of the tumor microenvironment (TME) has emerged as a tantalizing strategy to improve the efficacy of standard-of-care (SOC) treatments, particularly for hard-to-treat cancers such as glioblastoma. In this review, we explore how the distinct microenvironmental niches characteristic of the glioblastoma TME shape response to therapy. In particular, we delve into the interplay between tumor-associated macrophages (TAM) and glioblastoma cells within angiogenic and hypoxic niches, and interrogate their dynamic co-evolution upon SOC therapies that fuels malignancy. Resolving the complexity of therapy-induced alterations in the glioblastoma TME and their impact on disease relapse is a stepping stone to identify targetable pro-tumorigenic pathways and TAM subsets, and may open the way to efficient combination therapies that will improve clinical outcomes.