T cells may be able to kill acute myeloid leukemia (AML) through an unexpected route that bypasses the usual way tumors are “seen.” Researchers at The University of Texas MD Anderson Cancer Center report findings that help explain why AML often responds to immune-based interventions more strongly than many other cancers.
In the study, the team focused on how T cells eliminate leukemia cells when conventional tumor-recognition signals are absent. Typically, T cell receptors (TCRs) engage peptide fragments presented on major histocompatibility complex (MHC) molecules, forming a molecular lock-and-key that triggers cytotoxic killing. AML cells often evade immunity by downshifting or losing these antigen-presentation components.
To test whether MHC is truly required, the investigators removed MHC from AML cells. Contrary to prevailing expectations, activated T cells still destroyed the leukemia cells effectively. This MHC-independent killing pattern appeared across multiple AML cell models and in patient-derived samples, including cases with high-risk mutations and relapsed disease.
The researchers initially considered mechanisms resembling natural killer (NK) cell activity, since NK cells can recognize targets without MHC. However, perturbing several known NK-associated pathways did not abolish the effect, steering the team away from an NK-only explanation.
A key surprise emerged when the team disrupted TCR signaling. Even though MHC was unnecessary, eliminating the TCR component prevented T cell-mediated killing. Together, the results indicate a hybrid logic: the killing pathway is MHC-independent but TCR-dependent, using intact TCR activation rather than conventional peptide–MHC engagement.
To uncover the drivers behind this alternative route, the group ran a genome-wide CRISPR screen. The screen repeatedly highlighted CD64, a receptor commonly associated with early myeloid cells, alongside pathways tied to interferon-gamma signaling. When CD64 was removed, AML cells became resistant; when CD64 was introduced into otherwise less susceptible AML lines, sensitivity increased.
The work suggests that CD64 may provide a molecular foothold that enables T cell killing even when canonical recognition is impaired. The authors propose that this previously unrecognized mechanism could help explain AML’s responsiveness to certain immune therapies, including stem cell transplantation, which can reshape immune interactions.
Next steps will focus on mapping how CD64 and the TCR signaling machinery communicate to trigger cytotoxicity, and on determining whether the pathway can be harnessed to improve T cell therapies for AML and potentially other malignancies.
Subject of Research: T cell-mediated killing of acute myeloid leukemia (AML)
Article Title: (Not provided)
News Publication Date: July 15, 2026
Web References: https://www.pnas.org/doi/10.1073/pnas.2601232123
References: (Not provided)
Image Credits: The University of Texas MD Anderson Cancer Center
Keywords: acute myeloid leukemia, T cells, TCR signaling, MHC-independent killing, CD64, interferon-gamma, cancer immunotherapy, immune escape
Tags: acute myeloid leukemia immune evasioncancer immunology research at MD Andersonimmune response in relapsed AMLimmune system adaptability in hematologic cancersimmune-based therapies for AMLMHC-independent tumor cell killingnatural killer cell mechanisms in cancernovel immune pathways in AMLT cell cytotoxicity without MHCT cell receptor signaling in leukemiatumor recognition bypass mechanisms
