According to the anti-persecution charity Aid to the Church in Need (ACN), IS forces has been advancing on the predominantly Christian town of Sadad.
Islamic State has already captured towns as little as five miles away, and particularly wants to capture Sadad to murder the Christians there, utilise a nearby motorway linking the capital Damascus with the major northern city of Homs, and extract local oil reserves.
The militant group murdered 45 Christians when it last captured Sadad in 2013, before government forces recaptured the town after a few weeks.
The Syrian Orthodox Archbishop of Homs and Hama, Selwanos Boutros Alnemeh, said: "We are afraid that ISIS will conquer the town [of Sadad]... we would lose the centre of Christianity in our diocese."
And Fr Luka Awad, who assists Archbishop Alnemeh in gathering and distributing emergency aid, said: "When the ISIS fighters conquered Qaryatayn [another Christian town], they made the threat: 'We will kill all of the Christians in Sadad.'
"My people already experienced a genocide 100 years ago in 1915. Now in the 21st century, we don't need another.
"The people there still speak Aramaic, the language of Jesus.
"We have important churches there. It is really a centre of our Christian heritage. Its loss doesn't bear contemplating.
"We beg the international community to put an end to this war."
Government forces have now arrived and are engaging Islamic State militants.
