Eomes sustains progenitor CD4⁺ T helper cells to promote anti-tumor immunity during immunotherapy [scRNA]

CD4⁺ T helper (Th) cells contribute to tumor immunity, yet the subsets and differentiation programs involved remain unclear. Here, we show that the transcription factor Eomesodermin (Eomes) is essential for Th–mediated anti-tumor immunity by orchestrating the differentiation and maintenance of an exhausted-like Th cell lineage, which is transcriptionally and functionally distinct from conventional effector or memory Th subsets. This Eomes-dependent program is further enhanced by 4-1BB stimulation, promoting effective Th cell–mediated tumor control. The precursor subset of this lineage (pTh) expresses stemness-associated transcription factors, displays self-renewal capacity, and can differentiate into effector cells capable of controlling tumor growth. At the transcriptional level, Eomes supports the survival, metabolic fitness, and apoptotic resistance of this lineage. Notably, Eomes⁺ pTh cells are directly relevant to human cancer, being detected across multiple tumor types, exhibiting conserved transcriptional features, and representing the most expanded Th cell population upon immune checkpoint blockade therapy.