Lck, a member of the Src kinase family, is a non-receptor tyrosine kinase involved in immune cell activation, antigen recognition, tumor growth, and cytotoxic response. The enzyme has usually been linked to T lymphocyte activation upon antigen recognition. Lck activation is central to CD4, CD8, and NK activation. However, recently, it has become clearer that activating the enzyme in CD8 cells can be independent of antigen presentation and enhance the cytotoxic response. The role of Lck in NK cytotoxic function has been controversial in a similar fashion as the role of the enzyme in CAR T cells. Inhibiting tyrosine kinases has been a highly successful approach to treating hematologic malignancies. The inhibitors may be useful in treating other tumor types, and they may be useful to prevent cell exhaustion. New, more selective inhibitors have been documented, and they have shown interesting activities not only in tumor growth but in the treatment of autoimmune diseases, asthma, and graft vs. host disease. Drug repurposing and bioinformatics can aid in solving several unsolved issues about the role of Lck in cancer. In summary, the role of Lck in immune response and tumor growth is not a simple event and requires more research.

LCK, a member of the Scr kinase family, is a non-receptor tyrosine kinase involved in immune cell activation, antigen recognition, tumor growth, and cytotoxic response. The enzyme has usually been linked to T lymphocyte activation upon antigen recognition. Lck activation is central to CD4, CD8, and NK activation. However, recently, it has become clearer that activating the enzyme in CD8 cells can be independent of antigen presentation and enhance cytotoxic response. The role of Lck in NK cytotoxic function has been controversial in a similar fashion as the role of the enzyme in CAR T cells. Inhibition of Lck has been mainly to treat hematologic malignancies with a high rate of success. They may be useful in treating other tumor types, and they may be useful to prevent cell exhaustion. New, more selective inhibitors have been documented, and they have shown inter-esting activities not only in tumor growth but in the treatment of autoimmune diseases, asthma, and graft vs host disease. Drug repurposing and bioinformatics can aid in solving several unsolved is-sues on the role of Lck in cancer. In summary, the role of Lck in immune response and tumor growth is not a simple event and requires more research.

ORMDL proteins are essential negative regulators of the serine palmitoyltransferase (SPT) complex, thereby controlling the rate of de novo sphingolipid synthesis. Although mammalian ORMDLs undergo rapid turnover, the mechanisms regulating their stability remain unclear, with conflicting observations across studies. Here, we combined lipidomics, proteomics, and biochemical assays to investigate ORMDL regulation in HEK293, RPE‐1, and primary mouse bone marrow–derived mast cells (BMMCs). Inhibition of SPT by myriocin or of ceramide synthases by fumonisin B ₁ (FB ₁ ) profoundly altered sphingolipid composition but induced minimal global proteomic changes while consistently reducing ORMDL protein levels. In contrast, overexpression of a single‐chain SPT increased ORMDLs alongside elevated sphingolipids, an effect reversed by myriocin or FB ₁ . ORMDL loss closely correlated with ceramide depletion and, in HEK293 and RPE‐1 cells, was prevented by proteasome inhibition, whereas autophagy inhibition had no effect. In BMMCs, both pathways contributed to ORMDL regulation, consistent with high basal autophagy reflected by elevated LC3‐II. The p97/valosin‐containing protein ATPase was involved in the regulation of ORMDL turnover in all tested cell lines. Mutation of conserved asparagines (N11/N13) in ORMDL3, which mediate ceramide binding and stabilization of the inhibitory conformation, disrupted association with SPTLC1 and SPTLC2, mimicking myriocin‐induced complex dissociation, while FB ₁ had a weaker effect. Together, these findings suggest that ceramide depletion is the primary trigger for ORMDL degradation in HEK293, RPE‐1, and BMMCs and reveal a proteasome‐dependent pathway that can be supplemented by autophagy in cells with high basal autophagic activity.