Traumatic brain injury (TBI) and malignancies, despite their distinct nature, are characterized by similar immune responses, including the development of local and systemic inflammation and T-cell exhaustion. This article compares the role of immune checkpoints in the development of immune dysfunction in cancer and TBI, examines the contribution of the sympathetic nervous system to these changes, and discusses the relationship between local and systemic inflammation in these two conditions. Particular attention is paid to approaches to pharmacological modulation of inflammation and the impact on exhausted T-cells in these conditions. Comparison of inflammation and T-cell exhaustion in cancer and TBI highlights existing gaps in our understanding of immune regulation in TBI and points to areas requiring further investigation. Clarification of the immune mechanisms underlying the pathogenesis of TBI may facilitate the search for new diagnostic markers and lay the groundwork for the development of new therapeutic approaches for TBI treatment.