Overexpression of ICPMLs on tumor cells can be the result of different stimuli, either cell-autonomous stimuli or stimuli from the tumor microenvironment (TME). The mechanisms underlying the overexpression of ICPMLs on tumor cells have been most thoroughly investigated for PD-L1 and have been reviewed recently [
9]. As regards tumor cell-autonomous stimuli, overexpression of PD-L1 can be the result of intrachromosomal or extrachromosomal events. Copy number alterations in chromosomal region 9p24.1 that encompasses the loci for PD-L1 and PD-L2, inversions, deletions, translocations, generation of chimeric fusion transcripts, and disruption or mutation of the 3′-untranslated region of the
PD-L1 gene are intrachromosomal events that can lead to PD-L1 overexpression [
10,
11,
12]. Tumor cell-autonomous, extrachromosomal events are receptor-activating mutations or receptor overexpression [
13], gain-of-function or loss-of-function mutations affecting intracellular signaling molecules [
14,
15], activation or overexpression of transcription factors (e.g., hypoxia-inducible factor-α, signal transducer and activator of transcription (STAT) 3, MYC) [
16,
17,
18]. More recently, also epigenetic mechanisms have been reported to induce or contribute to the overexpression of tumor cell-associated PD-L1 [
19,
20]. Tumor cell-exogenous stimuli that can lead to the overexpression of PD-L1 are cytokines (e.g., interferon (IFN)-γ, tumor necrosis factor (TNF)-α) [
21,
22] and various other stimuli from the TME like hypoxia or pseudohypoxia [
18,
23], antitumor drugs (chemotherapeutics, targeted therapeutics) [
24] or metabolites (e.g., lactate) [
25]. While the mechanisms leading to the overexpression of other tumor cell-associated ICPMLs have been much less investigated, they appear to be similar to those for PD-L1. Thus, hypoxia or pseudohypoxia lead to the overexpression of B7-H4 [
26], CD70 [
27], CD47 [
28]. Antitumor drugs lead to the overexpression of CD70 and B7-H3 [
29,
30]. Activation of the Ras-Raf-MEK-extracellular signal-regulated kinase pathway leads to overexpression of CD155 and CD137 [
31,
32], Hedgehog signaling to overexpression of CD155 [
32], the Janus kinase 2-STAT3 pathway to overexpression of fibrinogen-like protein 1 (FGL1) [
33]. While the stimuli that induce overexpression of ICPMLs on tumor cells appear to be similar, in some instances subtle differences in the intracellular signaling pathways regulating the expression of two different ICPMLs have been observed [
34], suggesting that these differences may explain the different patterns of expression that have been observed between different tumor cell-associated ICPMLs (see
Section 3).