Interleukin-12 (IL12) enhances anti-tumor immunity when delivered locally within the tumor microenvironment. However, immunoregulatory elements within the tumor microenvironment are thought to dampen the effect of IL12 as an adjuvant. The objective of this study was to identify biochemical mechanisms of tumor-immune cell cross-talk that locally suppress the action of IL12. A high content in vitro assay was developed to quantify tumor-mediated suppression of the action of IL12 using a T helper type 1 cell line. Following an induction period, the melanoma cell model, B16F0, inhibited the cellular response to IL12 in vitro. This paracrine effect was not explained by induction of apoptosis or creation of a cytokine sink, despite both mechanisms at work within the co-culture assay. Secreted protein, acidic and rich in cysteine (SPARC); exosomes; and Wnt-inducible signaling protein-1 (WISP-1) were identified using a proteomics workflow and confirmed to be enriched in B16F0-conditioned media. Neutralization of WISP-1 recovered and recombinant WISP-1 dose-dependently inhibited the activity of Signal Transducer of Activated Tyrosine 4 (STAT4), a key transcription factor within the IL12 pathway, within the in vitro co-culture assay. Moreover, WISP-1 was expressed in vivo following intradermal challenge with B16F10 cells and exhibited an inverse dependence on tumor size.