Tumor infiltration with effector CD8⁺ T cells (T_eff) predicts longer recurrence-free survival in many types of human cancer, illustrating the broad significance of T_eff for effective immunosurveillance. Colorectal tumors with reduced accumulation of T_eff express low levels of T_eff-attracting chemokines such as CXCL10/IP10 and CCL5/RANTES. In this study, we investigated the feasibility of enhancing tumor production of T_eff-attracting chemokines as a cancer therapeutic strategy using a tissue explant culture system to analyze chemokine induction in intact tumor tissues. In different tumor explants, we observed highly heterogeneous responses to IFNα or poly-I:C (a TLR3 ligand) when they were applied individually. In contrast, a combination of IFNα and poly-I:C uniformly enhanced the production of CXCL10 and CCL5 in all tumor lesions. Moreover, these effects could be optimized by the further addition of COX inhibitors. Applying this triple combination also uniformly suppressed the production of CCL22/MDC, a chemokine associated with infiltration of T regulatory cells (T_reg). The T_eff-enhancing effects of this treatment occurred selectively in tumor tissues, as compared with tissues derived from tumor margins. These effects relied on the increased propensity of tumor-associated cells (mostly fibroblasts and infiltrating inflammatory cells) to hyperactivate NF-κB and produce T_eff-attracting chemokines in response to treatment, resulting in an enhanced ability of the treated tumors to attract T_eff cells and reduced ability to attract T_reg cells. Together, our findings suggest the feasibility of exploiting NF-κB hyperactivation in the tumor microenvironment to selectively enhance T_eff entry into colon tumors. Cancer Res; 72(15); 3735–43. ©2012 AACR.