TNF and neoplasm: The acidic conditions impair T cell activation and proliferation by disrupting key signaling pathways.44 Ex vivo studies have shown that low pH in the TME directly inhibits melanoma tumor-infiltrating lymphocytes (TILs) by reducing their proliferation, activation markers like p-STAT5 and p-ERK, and the production of cytokines such as IL-2, TNFα, and IFN-γ.