C-reactive protein (CRP) is an acute phase reactant synthesized by hepatocytes and released into the blood in response to inflammatory cytokines including interleukin-6 (IL-6). CRP is widely utilized as a marker for systemic inflammation in non-cancer-related conditions such as cardiovascular disease, infection and inflammation (Pepys and Hirschfield, 2003). Tumor-promoting inflammation is a hallmark of cancer pathogenesis and involves a tumor microenvironment (TME) shaped by various molecular and cellular interactions, prominently involving fibroblasts and innate immune cells. Such cells largely underlie production of IL-6 in the TME which is felt to contribute to elevated CRP in patients with cancer (Du Clos, 2000, Mauer et al., 2015). Thus, peripheral blood CRP, a routinely measured analyte, may provide a window into specific TME biology. The role of CRP has been investigated in a variety of cancer types, including urothelial carcinoma (UC) of the upper urinary tract and bladder. Several observational studies have demonstrated an association between high CRP levels and decreased survival in patients with bladder cancer (BCa) who underwent radical cystectomy or chemoradiotherapy (Hilmy et al., 2005, Saito and Kihara, 2011, Yoshida et al., 2008).

Immune checkpoint blockade (ICB) has revolutionized the treatment of UC (Cathomas et al., 2022). Due to the immune suppressive effects primarily from myeloid-derived suppressor cells (MDSCs) and regulatory T cells induced by tumor-promoting inflammation in the TME, several studies have explored the association between CRP and outcomes in patients treated with ICB and demonstrated worse outcomes in patients with higher baseline CRP levels (Gabrilovich et al., 2012, Greten and Grivennikov, 2019, Han et al., 2022). Given that several strategies such as targeting MDSCs, tumor-associated macrophages, cancer-associated fibroblasts, immunosuppressive cytokines including IL-6 and IL-1β (Hou et al., 2021, Huseni et al., 2023), are in development seeking to modulate tumor-promoting inflammation, peripheral blood CRP could potentially represent an approach to identify patients most suitable for such strategies. As ICB has now been integrated across the spectrum of clinical disease states of UC, a large-scale meta-analysis is needed to refine our understanding of the role of CRP. Thus, we performed a systematic review and meta-analysis to elucidate the prognostic role of CRP in patients with UC.