Cancer immunology research has been centered on how to generate anti-tumor immunity. However, unambiguous clinical evidence has shown that in advanced cancer patients, the tumors induce extensive immune system disorder, i.e., systemic inflammation. In this study, we investigated the impact of systemic inflammation on survival and efficacy of immunotherapy. We found that systemic inflammation drives mice health deterioration during disease progression to late stage and treating the systemic inflammation, with no need to inhibit tumor growth, improves health condition and extends survival. These findings suggest that systemic inflammation in advanced cancer might be an important therapeutic target. Methods 7-week old BALB/c mice were inoculated with 1 x106 C26 tumor cells subcutaneously. Mice body weight and health condition were measured starting 7 days after tumor inoculation. At various time points, peripheral blood was drawn, and immune cells was analyzed with flow cytometry; serum cytokines were measured with mouse cytokine array. Tumor bearing mice were treated with anti-PD1 antibody and anti-inflammation drugs and the treatment effect was monitored. Results Localized tumor growth progressively induces host immune system disorder with increase of Gr1+ cell population and decrease of CD3+ cell population in peripheral blood. When mice began to lose body weight, the cell percentage imbalance was enlarged (Gr1+ %: Naïve 7.90 ± 0.727 vs tumor 72.15 ± 4.143, p<0.0001; CD3+%: Naïve 41.18±2.023 vs tumor 9.18 ±0.249, p<0.0001). The immune cell imbalance along health deterioration (>15% body weight loss) further exacerbates (Gr1+ %: early 72.15 ± 4.143 vs late 93.83 ± 1.971, p=0.0032; CD3+ %: early 9.18±0.249 vs late 6.25±1.085, p=0.0392). In addition, pro-inflammatory cytokines such as IL-1, IL-6 and TNF-a increase expression in mouse serum accompanying health condition deterioration. More importantly, therapeutic interventions with anti-inflammation drug Ketorolac or by depletion of Gr1+ inflammatory cells, could reverse the deterioration process and significantly increase mice survival. Interestingly, when combined with anti-PD-1 antibody, treating systemic inflammation enhances the anti-tumor efficacy of the antibody. Conclusions Progressive systemic inflammation characterized by severe immune cell imbalance and overexpression of multiple inflammatory cytokines drives the rapid overall health deterioration of late stage cancer. Treating the systemic inflammation not only reverses health deterioration but also significantly increases survival. Therefore, targeting systemic inflammation might be a promising approach to the treatment of late stage cancer. Citation Format: Lingbing Zhang, Gennie Liu. Treatment of systemic inflammation significantly improves survival in a murine model that recapitulates the rapid health deterioration of advanced cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5590.