Lapatinib (L) is a dual EGFR/HER2 tyrosine-kinase inhibitor used in HER2+ metastatic breast cancer (BC), but its clinical benefit is <25%. We reported that soluble TNF (sTNF) induces trastuzumab (T) resistance by upregulating mucin 4 (MUC4), a transmembrane glycoprotein that shields T epitope on HER2, and that women with HER2+/MUC4+ BC have worse survival. Here, we studied the participation of sTNF and transmembrane TNF (tmTNF) in L resistance and the innate immune response (IIR) in JIMT-1, a T and L-resistant BC cell line. We used the dominant negative protein INB03 (DN) to selectively block sTNF and etanercept (E) to block both TNF isoforms. DN or E fail to inhibit tumor growth alone but, combined with L, tumor growth decreased in a 54% and 34% respectively (p<0.0001 vs. IgG). L+DN exhibited a stronger anti-tumor effect than L+E (p<0.05). Tumor-infiltrating immune cell analysis showed an increase in NK cell activation and degranulation and a decrease in myeloid-derived suppressor cells in L+E and L+DN treated tumors. Here, we show that TNF blockade overcomes L resistance and that TNF neutralization along with L treatment unleashes an anti-tumor IIR, suggesting MUC4 expression in patients with HER2+ BC as a potential biomarker of L resistance. Patients with HER2+/MUC4+ tumors undergoing L therapy would benefit from the addition of the selective sTNF inhibitor DN to overcome resistance, particularly patients with CNS metastasis since L and DN cross the blood brain barrier.