Targeting Dicer reprograms tumor-associated macrophages to promote anti-tumoral immunity in colorectal cancer liver metastasis.

BACKGROUND: Tumor-associated macrophages (TAMs) contribute significantly to immunosuppression in colorectal cancer liver metastasis (CRLM), leading to high aggressiveness and poor prognosis. However, the key molecules involved in shaping TAMs toward the pro-tumoral phenotype in CRLM remain unclear, limiting the development of macrophage-mediated immunotherapies for CRLM. RESULTS: In this study, we showed that DICER1 was highly expressed in TAMs and closely associated with M2 polarization in CRLM. Knockdown of Dicer, encoded by DICER1 in humans (or Dicer1 in mice), skewed macrophages toward an anti-tumoral M1 phenotype, with increased expression of pro-inflammatory cytokines and tumor cell phagocytosis, thereby suppressing tumor growth in mice. An M2 macrophage-targeting nanosystem was developed to deliver Dicer1 siRNA for selectively downregulating Dicer expression in M2 macrophages. In situ manipulation of TAMs with the nanoparticle exerted a significant anti-tumor effect with an improved immune microenvironment in a CRLM mouse model. Macrophage depletion experiments further suggested that this effect was largely dependent on the presence of TAMs. Mechanistically, Dicer inhibition reprogrammed M2-like macrophages through downregulation of miR-148a-3p and miR-1981-5p. CONCLUSION: Our study uncovered the central role of Dicer in the M2 polarization of TAMs, in turn suggesting a promising therapeutic strategy for CRLM.