CD209, a C-type lectin receptor expressed on tumor-infiltrating M2 macrophages and monocytes, functions as a myeloid-derived mechanical immune checkpoint that suppresses antitumor T-cell immunity by binding ICAM-2 on T cells to trigger ROCK1-ERM-mediated cortical stiffening, thereby destabilizing T-cell-APC conjugation and attenuating TCR signaling; therapeutic blockade of CD209 with neutralizing antibodies overcomes this suppression to achieve robust tumor regression across multiple models including immunotherapy-refractory cold tumors such as ovarian cancer and glioblastoma, while elevated CD209 expression in human cancers inversely correlates with CD8+ T-cell infiltration and predicts resistance to PD-1 blockade therapy.

Cancer immunotherapy has achieved durable clinical benefit in a subset of patients; however, most solid tumors—particularly immunologically “cold” tumors—remain refractory due to profound T-cell exclusion and dysfunction within the tumor microenvironment (TME). Here, we identify CD209 (DC-SIGN), a C-type lectin receptor expressed by tumor-infiltrating myeloid cells, as a previously unrecognized myeloid-derived mechanical immune checkpoint that suppresses antitumor T-cell immunity. Using human CD209 knock-in mice, we demonstrate that therapeutic blockade of CD209 markedly enhances T-cell infiltration and activation, resulting in robust tumor regression across multiple models, including ovarian cancer and glioblastoma. Mechanistically, CD209 directly engages intercellular adhesion molecule 2 (ICAM-2) on T cells, triggering ezrin/radixin/moesin (ERM) phosphorylation and increasing T-cell cortical stiffness. This biophysical reprogramming destabilizes T cell–antigen-presenting cell conjugation and attenuates T-cell receptor signaling. Analyses of human cancer datasets and primary tumor specimens reveal that elevated CD209 expression inversely correlates with CD8⁺ T-cell infiltration and is associated with reduced overall survival. Moreover, CD209 expression is significantly enriched in PD-1 therapy non-responders and positively correlates with TIDE (Tumor Immune Dysfunction and Exclusion) scores across multiple cancer types. Together, these findings establish CD209 as a central regulator of myeloid-driven T-cell mechanical dysfunction and highlight its potential as a therapeutic target and a candidate companion diagnostic biomarker for immunotherapy response.