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Abstract Y-box binding protein 1 (YBX1 or YB1) is a therapeutically relevant oncoprotein capable of RNA and DNA binding and mediating protein–protein interactions that drive proliferation, stemness, and resistance to platinum-based therapies. Given our previously published findings, the potential for YB1-driven cisplatin resistance in medulloblastoma (MB), and the limited studies exploring YB1-DNA repair protein interactions, we chose to investigate the role of YB1 in mediating radiation resistance in MB. MB, the most common pediatric malignant brain tumor, is treated with surgical resection, cranio-spinal radiation, and platinum-based chemotherapy, and could potentially benefit from YB1 inhibition. The role of YB1 in the response of MB to ionizing radiation (IR) has not yet been studied but remains relevant for determining potential anti-tumor synergy of YB1 inhibition with standard radiation therapy. We have previously shown that YB1 drives proliferation of cerebellar granular neural precursor cells (CGNPs) and murine Sonic Hedgehog (SHH) group MB cells. While others have demonstrated a link between YB1 and homologous recombination protein binding, functional and therapeutic implications remain unclear, particularly following IR-induced damage. Here we show that depleting YB1 in both SHH and Group 3 MB results not only in reduced proliferation but also synergizes with radiation due to differential response dynamics. YB1 silencing through shRNA followed by IR drives a predominantly NHEJ-dependent repair mechanism, leading to faster γH2AX resolution, premature cell cycle re-entry, checkpoint bypass, reduced proliferation, and increased senescence. These findings show that depleting YB1 in combination with radiation sensitizes SHH and Group 3 MB cells to radiation.

Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment promotes a compensatory neutrophil influx and that concomitant neutrophil inhibition is required to improve survival in GBM preclinical models.

Tumour-associated angiogenesis facilitates the growth of tumours. Here the authors show that integrin α3β1 promotes blood vessel formation in glioblastoma through calcium-mediated macropinocytosis and lysosomal exocytosis.

Elevated levels of interleukin-33 have been associated with poor prognosis in patients with glioma. Here the authors show that glioma-derived IL-33 modulates a pro-tumorigenic immune microenvironment by activating resident and recruiting peripheral innate immune cells.

The Sonic Hedgehog subgroup of medulloblastoma are characterised by the high infiltration of tumour-associated macrophages (TAMs). Here, the authors show that TAM numbers in patients are associated with better prognosis and that, consistently, in a murine model of medulloblastoma, these TAMs have anti-tumoural properties.

NOTCH signalling stimulates oligodendrocyte progenitor cell proliferation but how this regulates demyelinating disease is unclear. Here, the authors show that an IL-17 adaptor protein, Act1, interacts with the C-terminal fragment of NOTCH1 (NICD) to activate cell proliferation and an inflammatory response.