SLAMF6 Restrains T-Cell Function and Limits Antitumor Immunity

Immune checkpoint receptors such as PD-1 promote T-cell dysfunction in cancer. Although immune checkpoint blockade can restore antitumor immunity, many tumors fail to respond, highlighting the need to identify additional regulators of T-cell activity. Members of the signaling lymphocytic activation molecule (SLAM) family are homotypic, transmembrane receptors expressed broadly on hematopoietic cells, yet their roles in T-cell biology remain inconclusive, with both activating and inhibitory functions described. Li and colleagues provide genetic and functional evidence establishing SLAMF6 as a negative regulator of T-cell activation and antitumor immunity. Using Slamf6 –/– mice, the authors found that loss of Slamf6 enhanced CD4+ and CD8+ T-cell proliferation, cytokine production, and antigen-specific responses. These effects translated into improved antitumor immunity in vivo, as mice receiving adoptively transferred Slamf6−/− CD8+ T cells exhibited delayed E.G7 lymphoma tumor growth, increased T-cell accumulation, and elevated IFNγ and TNF production, demonstrating that SLAMF6 restrained CD8+ T-cell effector function. Mechanistically, SLAMF6 engaged in homotypic cis interactions on individual T cells, as shown by FRET analyses. To define downstream signaling pathways, key SLAM-associated effectors were silenced via siRNA. Knockdown of Ptpn6, which encodes SHP1, enhanced CD3 responses in wild-type T cells but not Slamf6–/– T cells, indicating that SLAMF6 suppresses TCR signaling primarily through SHP1. Similar regulatory mechanisms were observed in human T cells, as SLAMF6-deficient human T cells exhibited enhanced CD3-induced activation, protein tyrosine phosphorylation, and calcium flux. To assess therapeutic potential, the authors identified monoclonal antibodies that disrupted SLAMF6 cis interaction by 90% and induced up to a 10-fold increase in CD8+ T-cell activation. Consistent with these effects, the antibody suppressed tumor growth, increased infiltration of T cells, and reduced exhausted T-cell populations in tumor-bearing mice. Combined SLAMF6 and PD-L1 blockade produced the strongest antitumor effects. Together, these findings establish SLAMF6 as an inhibitory receptor that restrains T-cell function and highlight its potential as a complementary target for cancer immunotherapy.Li B, Zhong MC, Galindo CC, Dou J, Qian J, Tang Z, et al. SLAMF6 as a drug-targetable suppressor of T cell immunity against cancer. Nature 2026 Feb 11 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.