The clinical success of immune checkpoint inhibitors (ICIs) has highlighted the promise and challenges of cancer immunotherapy. However, many solid malignancies are resistant to ICIs, necessitating the development of novel therapies. Interleukin-12 (IL-12) is a promising cytokine for cancer therapy due to its direct effects on both innate and adaptive immunity. However, recombinant IL-12 (rIL-12) has unfavorable pharmacokinetics and a narrow therapeutic index, limiting its use. NHS-IL12, a fusion protein of IL-12 and NHS76 (human IgG1 antibody), targets single and double-stranded DNA in necrotic areas of solid tumors. Preclinical studies have shown that NHS-IL12 elicits significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8+ T lymphocytes, with engagement of myeloid immunity. NHS-IL12 is currently being evaluated clinically in combination with various therapeutic modalities, including chemotherapy, radiation therapy, immune checkpoint inhibition, vaccines, and epigenetic modulation. This review covers the preclinical and clinical studies involving NHS-IL12 for the treatment of solid malignancies, highlighting its potential as a novel and potent Th1-inducing immunocytokine.The clinical success of immune checkpoint inhibitors (ICIs) has highlighted the promise and challenges of cancer immunotherapy. However, many solid malignancies are resistant to ICIs, necessitating the development of novel therapies. Interleukin-12 (IL-12) is a promising cytokine for cancer therapy due to its direct effects on both innate and adaptive immunity. However, recombinant IL-12 (rIL-12) has unfavorable pharmacokinetics and a narrow therapeutic index, limiting its use. NHS-IL12, a fusion protein of IL-12 and NHS76 (human IgG1 antibody), targets single and double-stranded DNA in necrotic areas of solid tumors. Preclinical studies have shown that NHS-IL12 elicits significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8+ T lymphocytes, with engagement of myeloid immunity. NHS-IL12 is currently being evaluated clinically in combination with various therapeutic modalities, including chemotherapy, radiation therapy, immune checkpoint inhibition, vaccines, and epigenetic modulation. This review covers the preclinical and clinical studies involving NHS-IL12 for the treatment of solid malignancies, highlighting its potential as a novel and potent Th1-inducing immunocytokine.