TWEAK induces diverse cellular responses. including pro-inflammatory chemokine productions migration, proliferation, and cell death through the TWEAK receptor, Fn14. In the present Study we examined the effect of TWEAK or Fn 14 expression in tumor cells on tumor outgrowth in vivo. Administration of neutralizing anti-TWEAK mAb significantly reduced the frequency of tumor rejection and shortened the survival of mice intraperitoneally inoculated with TWEAK-sensitive Fn 14-expressing tumor cells. Moreover, anti-TWEAK mAb treatment promoted the subcutaneous growth of TWEAK-sensitive Fn 14-expressing tumor cells, and this promotion was abolished by the inhibition of macrophage infiltration but not NK cell depletion, In contrast, administration of anti-TWEAK mAb had no apparent effect on the growth of TWEAK-resistant tumor cells, even if tumor cells expressed Fn 14. On the other hand, TWEAK expression in tumor cells had no significant effect on subcutaneous tumor growth, These result, indicate that TWEAK mediates anti-tumor effect of macrophages in vivo. © 2005 Elsevier Inc. All rights reserved.