diff --git a/modules/nextflow/src/main/groovy/nextflow/cache/DefaultCacheStore.groovy b/modules/nextflow/src/main/groovy/nextflow/cache/DefaultCacheStore.groovy
index 9adea464a2..c8ea9dfd0e 100644
--- a/modules/nextflow/src/main/groovy/nextflow/cache/DefaultCacheStore.groovy
+++ b/modules/nextflow/src/main/groovy/nextflow/cache/DefaultCacheStore.groovy
@@ -20,6 +20,7 @@ import java.nio.file.Path
 
 import com.google.common.hash.HashCode
 import groovy.transform.CompileStatic
+import groovy.util.logging.Slf4j
 import nextflow.Const
 import nextflow.exception.AbortOperationException
 import nextflow.util.CacheHelper
@@ -32,6 +33,7 @@ import org.iq80.leveldb.impl.Iq80DBFactory
  *
  * @author Paolo Di Tommaso <paolo.ditommaso@gmail.com>
  */
+@Slf4j
 @CompileStatic
 class DefaultCacheStore implements CacheStore {
 
@@ -63,11 +65,31 @@ class DefaultCacheStore implements CacheStore {
         this.KEY_SIZE = CacheHelper.hasher('x').hash().asBytes().size()
         this.uniqueId = uniqueId
         this.runName = runName
-        this.baseDir = home ?: Const.appCacheDir.toAbsolutePath()
+        this.baseDir = home ?: resolveCacheBaseDir()
         this.dataDir = baseDir.resolve("cache/$uniqueId")
         this.indexFile = dataDir.resolve("index.$runName")
     }
 
+    /**
+     * Resolve the base directory for the cache DB.
+     *
+     * The {@code NXF_CACHE_DIR} environment variable can be used to redirect
+     * the LevelDB cache to a local filesystem that supports file locking
+     * (e.g. {@code export NXF_CACHE_DIR=/tmp/nxf-cache}) when the pipeline
+     * launch directory resides on a network filesystem such as NFS or Lustre.
+     *
+     * When {@code NXF_CACHE_DIR} is not set the default ({@code .nextflow/}
+     * relative to the launch directory) is used.
+     */
+    private static Path resolveCacheBaseDir() {
+        final override = System.getenv('NXF_CACHE_DIR')
+        if( override ) {
+            log.debug "Using NXF_CACHE_DIR for cache base directory: $override"
+            return Path.of(override).toAbsolutePath()
+        }
+        return Const.appCacheDir.toAbsolutePath()
+    }
+
     private void openDb() {
         // make sure the db path exists
         dataDir.mkdirs()
@@ -90,11 +112,18 @@ class DefaultCacheStore implements CacheStore {
                 throw new IOException(msg)
             }
             else {
+                // Log the underlying cause so it is visible in .nextflow.log for diagnosis.
+                log.debug "Failed to open LevelDB cache at path: $file -- cause: ${e.message}", e
                 msg = "Can't open cache DB: $file"
                 msg += '\n\n'
-                msg += "Nextflow needs to be executed in a shared file system that supports file locks.\n"
-                msg += "Alternatively, you can run it in a local directory and specify the shared work\n"
-                msg += "directory by using the `-w` command line option."
+                msg += "The Nextflow cache DB is located on a filesystem that does not support file locking.\n"
+                msg += "This is common when the pipeline is launched from a network filesystem (NFS, Lustre, GPFS, …).\n"
+                msg += "\nTo fix this, choose one of the following options:\n"
+                msg += "  1. Run Nextflow from a local directory and point the work directory to your shared\n"
+                msg += "     filesystem using the `-w` command line option.\n"
+                msg += "  2. Set the NXF_CACHE_DIR environment variable to a local path so that only the\n"
+                msg += "     cache DB is redirected to a lock-capable filesystem, e.g.:\n"
+                msg += "       export NXF_CACHE_DIR=/tmp/nxf-cache-\$USER"
                 throw new IOException(msg, e)
             }
         }