Objective: The Baculovirus Expression Vector System (BEVS) is an established eukaryotic platform for high-yield recombinant protein production and is widely utilized for generating vaccine antigens, including recombinant classical swine fever virus E2 glycoprotein, African swine fever virus structural proteins (p72, p30, and p54), and porcine reproductive and respiratory syndrome virus envelope proteins GP5 and M. These antigens interact with macrophage-associated receptors, including CD163 and CD206, to modulate immune responses through macrophage polarization. However, whether baculovirus vector-derived components intrinsically influence macrophage polarization remains unclear, raising concerns regarding potential impacts on biological activity, vaccine efficacy, and downstream purification strategies. Methods: In this study, an M2-like tumor-associated macrophage (TAM) model capable of repolarizing toward an M1-like phenotype was established to distinguish the transcriptomic effects of the baculovirus vector control (VC) from those of the recombinant antigen (A1). Comparative RNA sequencing, Gene Set Enrichment Analysis (GSEA), functional enrichment analyses, and linear regression analysis were performed to evaluate vector- and antigen-associated transcriptional responses. Results: Comprehensive transcriptomic analysis showed that VC treatment induced only minimal transcriptomic alterations, with limited immune-related pathway enrichment and expression profiles that remained highly similar to those of untreated M2-like TAMs. Furthermore, linear regression analysis demonstrated negligible correlations between VC-induced and A1-induced transcriptional responses indicating that the limited changes associated with the vector backbone did not correspond to the receptor-mediated immune responses elicited by the recombinant antigen. In contrast, A1 stimulation induced distinct transcriptional reprogramming characterized by enrichment of pro-inflammatory and immune-activation pathways and a shift toward an M1-like macrophage phenotype. Conclusions: These findings suggest the negligible correspondence between VC- and A1-induced transcriptional profiles further supports the transcriptomic noises and signals of the baculovirus vector and inserted proteins, reinforcing its suitability as a platform for macrophage-targeted vaccine development while providing a basis for future optimization of downstream purification strategies.