Inflammation in Penile Squamous Cell Carcinoma: A Comprehensive Review

Abstract

Inflammation appears to play a crucial role in the development and progression of penile cancer (PeCa). Two molecular pathways of PeCa are currently described: HPV-dependent and HPV-independent. The tumor immune microenvironment (TIME) of PeCa is characterized by the presence of tumor-associated macrophages, cancer-associated fibroblasts, and tumor-infiltrating lymphocytes. The components of the TIME produce pro-inflammatory cytokines and chemokines, which have been found to be overexpressed in PeCa tissues and are associated with tumor progression and unfavorable prognoses. Additionally, the nuclear factor kappa B (NF-κB) pathway and secreted phosphoprotein 1 (SPP1) have been implicated in PeCa pathogenesis. Elevated C-reactive protein (CRP) levels and the neutrophil-to-lymphocyte ratio (NLR) have been identified as potential prognostic biomarkers in PeCa. This overview presents the complex contribution of the inflammatory process and collates projects aimed at modulating TIME in PeCa.

Keywords: HPV; cytokines; inflammation; penile cancer; tumor immune microenvironment.

Figure 1

Selected cellular elements of the TIME interacting with PeCa cells. A tumor fragment is shown, along with a blood vessel supplying nutrients and cells from the body. Cellular processes are described in boxes. Abbreviations: M1, M2: TAM populations; NK: natural killer cell; Th1, Th2, Th17: CD8⁺ T-cell populations; CAF: cancer-associated fibroblast. Created using https://BioRender.com (accessed on 23 February 2025).

Figure 2

Enhancement or silencing of TIME inflammatory processes in PeCa in cytokine juxtaposition. The presence of pro-inflammatory cytokines (left panel) stimulates CD8⁺ cytotoxic lymphocytes, while the secretion of anti-inflammatory or immunomodulatory cytokines and the over-stimulation of CD8⁺ PDL-1 lymphocytes by cancer cells leads to the inhibition of the activity of these lymphocytes (right panel). Created using https://BioRender.com (accessed on 7 January 2025).

Figure 3

Compilation of inflammation-related elements as prognostic factors in PeCa. The factors shown in blue boxes determine the overall response of the body in the measurement of serum values. Local values analyzed within the tumor are shown in the dark-yellow boxes. Created using https://BioRender.com (accessed on 23 February 2025).