Differentiation of stem-like CD4 + T cells modulates early effector responses in colorectal cancer

Strategies to improve cancer immunotherapy have largely focused on the intratumor immunosuppressive microenvironment, whereas approaches to amplify peripheral T cells and promote tumor recruitment have not been thoroughly explored. Using imaging mass cytometry in patients with colorectal cancer (CRC), we observed T helper 1 (T H 1)–like immune architectures in mismatch repair–deficient tumors associated with response to anti–programmed cell death protein 1 (PD-1) immunotherapy. By contrast, mismatch repair–proficient (pMMR) tumors showed regulatory T–dominant spatial interactions. Clonal analyses revealed that stem-like CD4 + T cells differentiated into T H 1-like cells after PD-1 blockade. In pMMR CRC mouse models, combined OX40 agonist and PD-1 blockade suppressed tumor progression by expanding Il7r + early effector CD4 + intermediates in tumor-draining lymph nodes, promoting migration and connection with T H 1-like cells. This was accompanied by interferon-γ–dependent induction of immunostimulatory monocyte-macrophages and CD8 + effector T cells. These findings suggest that leveraging peripheral CD4 + T cell amplification may improve immunotherapy responses.