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Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60 Page 615

[30]
leading to mitochondrial dysfunction and, ultimately, apoptosis . Genetic ablation of FIP200 in naïve T
+
+
[30]
cells reduced CD8 and CD4 T cell infiltration and IFNg production . Recently, tumor-derived lactate was
+
also found to diminish TCA-intermediate recycling in CD8 T cells by inhibiting pyruvate carboxylase,
[31]
which shunts pyruvate to oxaloacetate . Pyruvate carboxylase is exceedingly important to maintain TCA
cycle anaplerosis in CD8 T cells because succinate is diverted from the TCA cycle to participate in
+
autocrine signaling . In addition to tumor-derived lactate suppressing CD8 T cell function, it also drives
[31]
+
the expansion and function of immunosuppressive cells. Tregs inhibit the function of anti-tumor immune
cells and require lactate to maintain their suppressor functions in the harsh TIME [32,33] . Moreover, lactate
produced by cervical cancer cells supports immunosuppressive macrophages by regulating anti-
inflammatory cytokine production and HIF1a expression . Taken together, these data highlight that
[34]
tumor-derived lactate not only directly inhibits effector T cell functions, but also indirectly through
supporting immunosuppressive cell populations. As such, multiple reports have examined the feasibility of
inhibiting tumor-intrinsic lactate metabolism in combination with anti-PD-1/PD-L1 therapy.
Several correlative studies through bioinformatic analyses have demonstrated that targeting lactic acid
metabolism might overcome ICB resistance and yield better patient outcomes. High LDH expression has
been evaluated as a selection criterion for and predicting response to ICB therapy [35-39] . Similarly, other
lactate-related genes have been correlated with the expression of immune checkpoint proteins, CD8 T cell
+
infiltration, and resistance to ICB in breast cancer . Moreover, decreased glycolytic flux in melanoma
[40]
patients treated with anti-PD-1 therapy was associated with increased probability of progression-free
[41]
survival .
In addition to bioinformatics studies, numerous reports indicate that inhibiting tumor-intrinsic lactic acid
metabolism in combination with anti-PD-1/PD-L1 therapies combats resistance and increases efficacy.
MCT4 is regulated at the mRNA level by the demethylase alkB homolog 5 (ALKBH5) . Genetic or
[42]
pharmacologic inhibition of ALKBH5 reduces intratumoral lactate concentration and the number of Tregs
and MDSCs, but has no effect on the number of infiltrating cytotoxic T cells . Furthermore, utilizing a
[42]
small molecular inhibitor of ALKBH5 significantly improved the efficacy of anti-PD-1 treatment in murine
[42]
melanoma tumors . Consistent with the findings that lactic acid benefits immunosuppressive cells,
researchers found that lactic acid produced by high-glycolytic tumors drove expression of PD-1 on Tregs,
+
[43]
but not CD8 T cells, leading to anti-PD-1 resistance . However, inhibiting either LDHA in tumors or
MCT1 in Tregs combined with anti-PD-1 therapy reversed these effects . In addition to inhibiting lactic
[43]
acid production and/or lactate import, antagonizing intracellular lactate signaling in malignant cells
through HCAR1 also promotes anti-tumor effects . Abrogating HCAR1-mediated lactate signaling
[44]
sensitized tumors to anti-PD-1 and metformin treatment, leading to reduced tumor volume and increased
CD8 T cell infiltration and IFNg production .
[44]
+
While a plethora of evidence supports the notion that lactic acid production by tumors and accumulation in
T cells drives oncogenesis, a few reports contradict this idea. In mouse melanoma tumors, blocking the
export of lactate and H ions through MCT1 and MCT4 reduced the acidification of the TIME . While
+
[41]
blocking MCT1 and 4 in T cells decreased lactate secretion and glucose uptake, it surprisingly did not
impair IFNg production , which contrasts with other findings that accumulation of intracellular lactic acid
[41]
promotes acidification and dampens effector functions [21,22,24] . The authors found that inhibiting MCT1 and
4 activities in T cells increased glucose flux through the TCA cycle and increased oxygen consumption, thus
+
[41]
providing an explanation as to why CD8 T cell effector functions were preserved . Moreover,
pharmacologically inhibiting MCT1 and 4 in combination with anti-PD-1 treatment resulted in increased
[41]
efficacy and decreased tumor volume . The results from these findings are indeed surprising given the