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Casitas B lymphoma-b (Cbl-b) is an E3 ubiquitin ligase that serves as a critical brake on immune cell activations. It negatively fine-tunes immune responses through ubiquitination of signaling proteins. Cbl-b deficiency in mice leads to spontaneous tumor rejection and induces only mild, non-lethal autoimmunity, highlighting its potential as a promising immunotherapy target. NX-1607 is the first oral small molecule inhibitor of Cbl-b and it is currently in phase I clinical trial. A recent publication employed high-throughput drug combination screening to systematically elucidate the molecular pathways by which NX-1607 enhances T cell activation. The authors administered 81 well-characterized inhibitors to Jurkat T cells under CD3-stimulated and unstimulated conditions in the presence of NX-1607. Inhibitors of the MAPK/ERK pathway significantly attenuated NX-1607-enhanced T cell activation as indicated by CD69 markers. Proto-oncogene tyrosine-protein kinase Src (SRC) family kinase inhibitors also reduced both CD69 activation markers and the phosphorylation of PLCγ1 and HCLS1 which are upstream of MAPK/ERK pathways. These findings were validated in an immunocompetent B-cell lymphoma mouse model, where NX-1607 consistently upregulated PLCγ1 and ERK phosphorylation. Together, this work delineates a PLCγ1-MAPK/ERK axis through which Cbl-b inhibition unleashes T cell activation, providing critical insight for the development of NX-1607 based immunotherapy.