Taken together, our study demonstrated that mature TLSs in ESCC facilitated immune cell cooperation and provided a privileged micro‐niche for B cells undergoing full differentiation, which further induced CD4+ T cell activation in TLSs and effective recruitment of CD8+ T cells in tumour regions to generate and sustain effective and memory anti‐tumour humoral and cellular immunity, and improve ESCC prognosis. Here, CD4 is linked to esophageal squamous cell carcinoma.