The Notch signaling pathway plays multiple roles in driving T-cell fate decisions,
proliferation, and aberrant growth. NF-kB is a cell-context key player interconnected
with Notch signaling either in physiological or in pathological conditions. This review
focuses on how themultilayered crosstalk between different Notches and NF-kB subunits
may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg)
cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a
pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor
growth. A future challenge is represented by further dissection of both Notch and NF-kB
pathways and consequences of their intersection in tumor-associated Treg biology. This
may shed light on themolecularmechanisms regulating Treg cell expansion andmigration
to peripheral lymphoid organs thought to facilitate tumor development and still to be
explored. In so doing, new opportunities for combined and/or more selective therapeutic
Q25 approaches to improve anticancer immunity may be found
