IL-6/CD147-augmented CAR macrophages enhance the antitumor activity of CAR-T cells in solid tumor models

Solid tumors remain challenging for cellular immunotherapy, and CAR-T or CAR-M cells alone often have limited efficacy. Combining these approaches may improve therapeutic activity; however, our previous in vitro study observed increased IL-6, while extracellular matrix (ECM) barriers can restrict immune-cell access. We engineered IL6-CD147 CAR-M, a synthetic IL-6-responsive macrophage construct designed to couple an IL-6-binding scFv to a CD147-containing module. Following IL-6 stimulation, IL6-CD147 CAR-M showed increased MMP-2, MMP-9, MMP-11, and MMP-13 transcripts and proteins. A CD147-deletion control did not reproduce the enhanced MMP transcriptional response, and GM6001 reduced CAR-T cell migration through Matrigel toward IL6-CD147 CAR-M-conditioned medium. In defined 80:20 mixed-antigen tumor models, IL6-CD147 CAR-M plus CAR-T increased tumor killing and inflammatory/cytotoxic mediators while reducing detectable extracellular IL-6. In vivo, combined therapy reduced tumor burden, prolonged survival, increased immune-cell infiltration, altered immune composition, and was not associated with overt histopathological abnormalities in the examined major organs at the assessed time points. These findings support further evaluation of an IL-6-responsive, CD147-containing CAR-M strategy; proximal receptor signaling and the mechanism underlying reduced extracellular IL-6 remain unresolved.