This review summarizes preclinical and clinical studies of NHS-IL12, a tumor-targeting immunocytokine composed of interleukin-12 (IL-12) and an antibody (NHS76) that targets DNA in necrotic areas of solid tumors. IL-12 is a cytokine that stimulates both innate and adaptive immunity, but its use as a cancer therapy is limited by poor pharmacokinetics and a narrow therapeutic index. NHS-IL12 is designed to enhance IL-12's activity by directing it to the tumor microenvironment (TME), where it can activate NK and CD8+ T cells, leading to tumor suppression. Preclinical studies showed that NHS-IL12 elicited significant Th1 immune activation and tumor suppressive effects, with engagement of myeloid immunity. NHS-IL12 is currently being evaluated in combination with various therapeutic modalities, including chemotherapy, radiation therapy, immune checkpoint inhibition, vaccines, and epigenetic modulation. In clinical trials, NHS-IL12 was well tolerated up to a dose of 16.8 μg/kg, with the recommended dose for phase II studies. Patients treated with NHS-IL12 showed increased frequencies of activated NK and NKT cells, and decreased plasmacytoid dendritic cells. The combination of NHS-IL12 with other therapies, such as checkpoint inhibitors and epigenetic modifiers, showed promising results in preclinical and clinical studies. For example, NHS-IL12 combined with bintrafusp alfa (αPD-L1/TGFβRII) and the HPV16 E6/E7 vaccine PDS0101 showed significant tumor regression and increased survival in patients with HPV-associated malignancies. Additionally, NHS-IL12 combined with entinostat showed enhanced antitumor activity by increasing tumor-infiltrating CD8+ T cells and decreasing Tregs. Overall, NHS-IL12 has shown promise as a tumor-targeting immunocytokine with the potential to overcome resistance to immune checkpoint inhibitors and other therapies. The combination of NHS-IL12 with other agents is being evaluated in ongoing clinical trials for the treatment of solid malignancies.This review summarizes preclinical and clinical studies of NHS-IL12, a tumor-targeting immunocytokine composed of interleukin-12 (IL-12) and an antibody (NHS76) that targets DNA in necrotic areas of solid tumors. IL-12 is a cytokine that stimulates both innate and adaptive immunity, but its use as a cancer therapy is limited by poor pharmacokinetics and a narrow therapeutic index. NHS-IL12 is designed to enhance IL-12's activity by directing it to the tumor microenvironment (TME), where it can activate NK and CD8+ T cells, leading to tumor suppression. Preclinical studies showed that NHS-IL12 elicited significant Th1 immune activation and tumor suppressive effects, with engagement of myeloid immunity. NHS-IL12 is currently being evaluated in combination with various therapeutic modalities, including chemotherapy, radiation therapy, immune checkpoint inhibition, vaccines, and epigenetic modulation. In clinical trials, NHS-IL12 was well tolerated up to a dose of 16.8 μg/kg, with the recommended dose for phase II studies. Patients treated with NHS-IL12 showed increased frequencies of activated NK and NKT cells, and decreased plasmacytoid dendritic cells. The combination of NHS-IL12 with other therapies, such as checkpoint inhibitors and epigenetic modifiers, showed promising results in preclinical and clinical studies. For example, NHS-IL12 combined with bintrafusp alfa (αPD-L1/TGFβRII) and the HPV16 E6/E7 vaccine PDS0101 showed significant tumor regression and increased survival in patients with HPV-associated malignancies. Additionally, NHS-IL12 combined with entinostat showed enhanced antitumor activity by increasing tumor-infiltrating CD8+ T cells and decreasing Tregs. Overall, NHS-IL12 has shown promise as a tumor-targeting immunocytokine with the potential to overcome resistance to immune checkpoint inhibitors and other therapies. The combination of NHS-IL12 with other agents is being evaluated in ongoing clinical trials for the treatment of solid malignancies.