DESTINY-Breast03 demonstrated that 50% of HER2+ metastatic breast cancer (BC) patients were progression-free after 24 months of treatment with trastuzumab-deruxtecan (T-DXd). However, most progress on treatment and die. We have shown that mucin 4 (MUC4) expression, induced by soluble TNF (sTNF), is an independent biomarker of poor response to trastuzumab and the main mediator of resistance to it in HER2+ BC. We also proved that blocking sTNF with INB03 (DN) decreases MUC4 expression and overcomes trastuzumab resistance. We studied whether blocking sTNF with DN enhances the antitumor activity and immune response associated with T-DXd. Nude mice bearing the trastuzumab-resistant human breast tumor JIMT-1 (HER2+MUC4+), were treated with IgG 5 mg/kg, T-DXd 5, 2.5 or 1.25 mg/kg, DN 10 mg/kg, or the combinations. IgG and T-DXd were administered i.v. on days 0, 7, and 14. DN was administered i.p. twice a week for 3 weeks. We analyzed the number of mitoses by HE staining and tumor-infiltrating leukocytes by flow cytometry. The dose-response curves showed tumor growth inhibition of 83% (T-DXd 5 mg/kg), 61% (T-DXd 2.5 mg/kg), and 37% (T-DXd 1.25 mg/kg), versus IgG. Adding DN enhanced this inhibition, increasing it to 98%, 81% and 73%, respectively. T-DXd 1.25 mg/kg + DN achieved an antitumor effect similar to T-DXd 5 mg/kg alone. Also, it reduced the number of mitoses and promoted an effective antitumor immune response mediated by macrophages and NK cells, compared to T-DXd 1.25 mg/kg alone. The combined therapies were well-tolerated, with no signs of toxicity. We conclude that adding DN could allow for a reduction in the optimal dose of T-DXd without compromising antitumor efficacy. As sTNF and MUC4 expression have shown to be relevant players in the response to T-DXd, we propose that patients with HER2+MUC4+ BC, or those who have progressed on T-DXd treatment could benefit from adding sTNF-blocking agents to enhance T-DXd antitumor effect and reduce its associated toxicity.