Hypoxia, Autophagy and Immune Escape in the Tumor Microenvironment: From Mechanisms to Therapeutic Targeting

Tumor hypoxia is a defining hallmark of solid cancers that profoundly influences tumor progression, genomic instability, and therapeutic response. Beyond its classical roles in angiogenesis and metabolic reprogramming, hypoxia has emerged as a central determinant of the tumor immune microenvironment (TME), promoting immune exclusion and resistance to immunotherapy. Our work has uncovered tumor cell–intrinsic mechanisms by which hypoxia drives immune escape. We identified hypoxia-induced autophagy as a key adaptive response that enables tumor cells to resist natural killer (NK) and cytotoxic T lymphocyte (CTL)–mediated killing. Under hypoxic stress, autophagy selectively degrades NK-derived granzyme B, neutralizing effector cytotoxicity, while genetic or pharmacologic inhibition of autophagy restores immune-mediated killing and enhances tumor regression in vivo. Furthermore, we demonstrated that Vps34 inhibition, a central regulator of autophagy and vesicular trafficking, converts poorly infiltrated “cold” tumors into inflamed “hot” tumors enriched in NK, CD4+, and CD8+ effector T cells, thereby potentiating the efficacy of PD‑1/PD‑L1 checkpoint blockade across multiple tumor models. Recently, we identified the atypical chemokine receptor ACKR2 as a hypoxia-inducible, HIF-1α–dependent checkpoint that restricts chemokine availability and limits immune infiltration. Targeting ACKR2 alleviates immune exclusion and synergizes with PD-1 blockades to induce tumor regression in otherwise refractory tumors. Collectively, these studies establish a coherent model in which hypoxia and its downstream stress-response pathways act as master regulators of tumor immune evasion. By rewiring autophagy and chemokine signaling, hypoxia shapes the immune landscape of solid tumors and defines responses to immunotherapy. Targeting these pathways represents a compelling strategy to overcome immune resistance and expand the clinical benefit of checkpoint inhibitor therapies.