Background <p>Bone-invasive Pituitary Neuroendocrine Tumors (BI PitNETs) epitomize an aggressive subtype of pituitary tumors characterized by bone invasion, culminating in extensive skull base bone destruction and fragmentation. This infiltration poses a significant surgical risk due to potential damage to vital nerves and arteries. However, the mechanisms underlying bone invasion caused by PitNETs remain elusive, and effective interventions for PitNET-induced bone invasion are lacking in clinical practice.</p> Methods <p>In this study, we performed single-cell (<i>n</i> = 87,287) RNA sequencing on 10 cases of bone-invasive PitNETs and 5 cases of non-bone-invasion PitNETs (Non-BI PitNETs). We identified various cell types and determined their interactions through cell-cell communication analysis, which was further validated experimentally.</p> Results <p>We identified a novel TNF-α⁺ TAM macrophage subset. BI PitNETs showed increased IL-34 secretion, impacting TNF-α⁺ TAMs via the IL34/CSF1R axis, leading to TNF-α production. TNF-α⁺ TAMs, in turn, communicate with <i>CD14</i>⁺ monocytes to promote their differentiation into osteoclasts and leading to bone invasion. In addition, we defined a gene signature for TNF-α⁺ TAM to guide the clinical prognosis prediction of BI PitNETs.</p> Conclusions <p>Our study elucidates the tumor microenvironment changes in bone invasion and identifies the critical role of TNF-α⁺ TAMs in promoting bone invasion of PitNETs, laying a foundation for developing new molecular markers or therapeutic agents targeting BI PitNETs.</p>