The Antitumor Cytotoxic Response: If the Killer Cells Play the Music, the Microenvironmental Hypoxia Plays the Tune.

The immune system is a potent defense mechanism regulating tumor development and progression. However, immune cells are often functionally compromised in cancer patients, and tumor rejection does not follow successful induction of a CTL response. This is, in part, due to the existing conflict between the tumor system and an unfavorable tumor microenvironment (TME) that is able to neutralize or paralyze the immune system of the host. The recent advances in the field of immune checkpoint inhibitors have changed the focus from targeting the tumor to targeting T lymphocytes. It has been well established that the TME and associated multiple factors contribute to the failures in cancer therapies, including immunotherapy. In this regard, hypoxia, which is a hallmark of solid tumors, is strongly associated with advanced disease stages and poor clinical outcomes. Hypoxia plays a crucial role in tumor promotion and immune escape by conferring tumor resistance, immunosuppression, and tumor heterogeneity, which contribute to the generation of diverse cancer invasion programs and enhanced stroma plasticity. Tumor hypoxic stress interferes with the mesenchymal transition EMT, conferring to cancer cells a high degree of plasticity and the capacity to escape from immune surveillance. Tumors have been also shown to take advantage of hypoxic conditions that impede normal cells. Thus, tumor progression may be mediated by hypoxia-induced phenotypic changes and subsequent clonal selection of malignant cells that overexpress hypoxia-responsive molecules, such as HIF-1α. Currently, the resistance of tumor cells to cell-mediated cytotoxicity remains a drawback in the immunotherapy of cancer, and its molecular basis is poorly understood. In this review, I focus on hypoxia as a key process that evolved in the TME, and I discuss how solid tumors use hypoxic stress as a potent saboteur of the antitumor immune reaction by shaping a compromised cytotoxic cell function through the alteration of tumor target susceptibility to cell-mediated cytotoxicity. Exploiting hypoxia-associated tumor escape capacities may hold promise for attenuating tumor heterogeneity and plasticity, overcoming alteration of antitumor cytotoxic response and improving its effectiveness in cancer patients.