The discovery of immune checkpoint inhibitors (ICIs) has ushered a new era for
immunotherapy against malignant tumors through the killing effects of cytotoxic
T lymphocytes in the tumor microenvironment (TME), resulting in long-lasting
tumor suppression and regression. Nevertheless, given that ICIs are highly
dependent on T cells in the TME and that most tumors lack T-cell infiltration,
promoting the conversion of such immunosuppressive “cold” tumors to “hot” tumors
is currently a key challenge in tumor immunotherapy. Herein, we systematically
outlined the mechanisms underlying the formation of the immunosuppressive TME in
cold tumors, including the role of immunosuppressive cells, impaired antigen
presentation, transforming growth factor-β, STAT3 signaling, adenosine, and
interferon-γ signaling. Moreover, therapeutic strategies for promoting cold
tumors to hot tumors with adequate T-cell infiltration were also discussed.
Finally, the prospects of therapeutic tools such as oncolytic viruses,
nanoparticles, and photothermal therapy in restoring immune activity in cold
tumors were thoroughly reviewed.