The hypoxic tumor microenvironment has been implicated in immune escape, but the underlying mechanism remains elusive. Using an in vitro culture system modeling human T cell dysfunction and exhaustion in triple-negative breast cancer (TNBC), we find that hypoxia suppresses immune effector gene expression, including in T and NK cells, resulting in immune effector cell dysfunction and resistance to immunotherapy. We demonstrate that hypoxia-induced factor 1α (HIF1α) interaction with HDAC1 and concurrent PRC2 dependency causes chromatin remolding resulting in epigenetic suppression of effector genes and subsequent immune dysfunction. Targeting HIF1α and the associated epigenetic machinery can reverse the immune effector dysfunction and overcome resistance to PD-1 blockade, as demonstrated both in vitro and in vivo using syngeneic and humanized mice models. These findings identify a HIF1α-mediated epigenetic mechanism in immune dysfunction and provide a potential strategy to overcome immune resistance in TNBC.

Accurate segregation of chromosomes during anaphase relies on the central spindle and its regulators. A newly raised concept of the central spindle, the bridging fiber, shows that sliding of antiparallel microtubules (MTs) within the bridging fiber promotes chromosome segregation. However, the regulators of the bridging fiber and its regulatory mechanism on MTs sliding remain largely unknown. In this study, the non‐motor microtubule‐associated protein, hyaluronan‐mediated motility receptor (HMMR), is identified as a novel regulator of the bridging fiber. It then identifies that HMMR regulates MTs sliding within the bridging fiber by cooperating with its binding partner HSET. By utilizing a laser‐based cell ablation system and photoactivation approach, the study's results reveal that depletion of HMMR causes an inhibitory effect on MTs sliding within the bridging fiber and disrupts the forced uniformity on the kinetochore‐attached microtubules‐formed fibers (k‐fibers). These are created by suppressing the dynamics of HSET, which functions in transiting the force from sliding of bridging MTs to the k‐fiber. This study sheds new light on the novel regulatory mechanism of MTs sliding within the bridging fiber by HMMR and HSET and uncovers the role of HMMR in chromosome segregation during anaphase.