Understanding why leukemia so reliably outsmarts the immune system is one of oncology's most consequential puzzles — and a comprehensive new review in Frontiers in Immunology zeroes in on a critical culprit: regulatory T cells (Tregs) that cancer cells effectively conscript to suppress anti-tumor immunity. This immunological subversion may explain why even sophisticated cellular therapies sometimes fall short.
The review systematically maps Treg behavior across four distinct leukemia types — AML, ALL, CML, and CLL — revealing that the bone marrow microenvironment functions as an immunosuppressive fortress actively maintained by leukemic blasts. Three molecular axes emerge as central to this suppression: the CCL22/CCR4 chemokine signaling pathway that recruits Tregs to tumor sites; the CD39/CD73 adenosine cascade that metabolically disables effector immune cells; and IDO-mediated tryptophan depletion that starves immune responses of an essential amino acid. The review also highlights a clinically inconvenient finding — Treg infiltration carries contradictory prognostic significance depending on leukemia subtype, complicating any universal therapeutic approach. On the treatment side, Treg-depleting antibodies such as mogamulizumab and RG6292 are assessed alongside venetoclax, hypomethylating agents, and tyrosine kinase inhibitors that incidentally reshape the Treg landscape.
This work consolidates a rapidly evolving literature into an analytically useful framework, though as a narrative review it carries the inherent limitations of selective source inclusion and absence of meta-analytic rigor. The finding that CAR-T and other cellular therapies face active Treg-mediated resistance within the tumor microenvironment is particularly important — it suggests that combination strategies pairing cellular therapy with Treg modulation may be necessary rather than optional. For the broader immunotherapy field, this review reinforces an emerging consensus: durable leukemia remission likely requires reengineering the immunosuppressive niche, not just targeting the malignant clone itself. Incrementally confirmatory in its mechanistic sections, it is clinically forward-looking in its therapeutic framing.