The BCL-2-tumor microenvironment axis: Mechanisms of immune suppression, resistance, and pathways to therapeutic...

The B-cell lymphoma 2 (BCL-2) family of proteins plays a central role in regulating apoptosis and has emerged as a key therapeutic target in oncology since the FDA approval of venetoclax in 2016. Within the tumor microenvironment (TME), intricate cellular and molecular interactions alter apoptotic signaling by upregulating anti-apoptotic BCL-2 members, thereby promoting tumor cell survival, immune evasion and therapy resistance. This review critically examines how anti-apoptotic BCL-2 proteins sustain a pro-tumor TME by supporting immunosuppressive populations such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), while suppressing tumor-infiltrating lymphocyte activity and driving metabolic reprogramming that enhances cancer cell fitness. Furthermore, biophysical and biochemical stressors in the TME-including hypoxia, angiogenesis, oxidative imbalance, and osmotic stress further modulate BCL-2 expression, reinforcing tumor progression and treatment resistance. Recent advances demonstrate that pharmacological inhibition or genetic modulation of BCL-2 family members-particularly targeting BCL-2, BCL-XL, or MCL-1, or activating pro-apoptotic mediators such as NOXA can reprogram the TME from an immunosuppressive ("cold") to an immune-responsive ("hot") phenotype. This transition enhances anti-tumor immunity, increases cytotoxic infiltration, and potentiates the efficacy of immunotherapeutic approaches, including PD-L1 blockade. Overall, this review provides an integrated perspective on how BCL-2 family signaling dynamically interacts with the TME to sustain malignancy and highlights the therapeutic potential of BCL-2 inhibition in reshaping the immune landscape and overcoming resistance across cancer types.