From immune exclusion to exhaustion: tumor microenvironment drives therapy response

The tumor microenvironment (TME) is increasingly recognized as a dynamic regulator of cancer progression and therapeutic resistance. Far from being a passive scaffold, the TME comprises diverse immune and stromal components, including cancer-associated fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages, dysfunctional vasculature, and metabolic stressors, that collectively shape tumor evolution and modulate treatment response. In this review, we explore how spatial immune exclusion, immune cell dysfunction, hypoxia, and metabolic reprogramming create barriers to effective therapy, particularly in tumors refractory to immune checkpoint inhibition. We detail the molecular and cellular mechanisms by which the TME enforces immune suppression and dampens the efficacy of chemotherapy, radiotherapy, and immunotherapy. Moreover, we highlight emerging strategies to therapeutically reprogram the TME, including anti-fibrotic therapies, vascular normalization, myeloid reprogramming, metabolic modulation, and novel platforms such as oncolytic viruses, nanoparticles, and bispecific antibodies. By dissecting both established and innovative approaches, we emphasize the importance of combinatorial and context-specific interventions aimed at increasing immune accessibility and functional competence in selected contexts, thereby improving the likelihood of therapy responsiveness. A deeper understanding of the TME's complexity offers critical opportunities to overcome resistance and improve outcomes across cancer types.