fig1

Figure 1. Main Mechanisms of Resistance (primary or secondary) to ICI. There are three different classifications or models summarizing the main mechanisms of resistance to ICI. The first classification (blue triangles) describes the response to ICI in relationship to markers of EMT^[10]: the more tumors show a status of EMT, the lesser they respond to ICI. The second classification associates the degree and type of fibrosis with responses to ICI (grey boxes)^[8]: response to ICI is generally observed in conditions with immune-enriched fibrotic and non-fibrotic conditions. By contrast, immune-depleted or fibrotic conditions are not responsive to ICI. The third classification is based on the presence of specific immune cells or markers (red boxes)^[5,6]: responses to ICI are commonly observed in patients with immune-inflamed conditions (characterized by a high CD8⁺/T_reg cell ratio, B cells and TLS-rich tissues); conversely, responses are reduced in immune-excluded conditions (characterized by high vascular stroma content with fibrosis, chemokines, such as CCL, CCL2, CCL5, CCL13, CCL22, or cytokines TGF-β). Limited or no responses to ICI are observed in patients with an immune-deserted tumor microenvironment (lacking T cell priming, exhibiting tolerance, and displaying CAF-related markers). While T_reg cells (green box) can be found in each of these conditions, their highest quantity and functional role are observed in either immune-excluded conditions or in immune-enriched fibrotic tissues. ICI: Immune checkpoint inhibitor; EMT: epithelial-mesenchymal transition; TLS: tertiary lymphoid structure; CCL: chemokine c-c-motif ligand; TGF-β: transforming growth factor beta; CAF: cancer-associated fibrosis.