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The development and progression of hepatocellular carcinoma (HCC) are dependent on its local microenvironment. Hypoxia and inflammation are two critical factors that shape the HCC microenvironment; however, the interplay between the two factors and the involvement of cancer cells under such conditions remain poorly understood. We found that tumor‐associated macrophages, the primary proinflammatory cells within tumors, secreted more interleukin 1β (IL‐1β) under moderate hypoxic conditions due to increased stability of hypoxia inducible factor 1α (HIF‐1α). Under persistent and severe hypoxia, we found that the necrotic debris of HCC cells induced potent IL‐1β release by tumor‐associated macrophages with an M2 phenotype. We further confirmed that the necrotic debris–induced IL‐1β secretion was mediated through Toll‐like receptor 4/TIR domain–containing adapter‐inducing interferon‐β/nuclear …